rs137868995

chr9-133519002-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM1 PP5_Very_Strong BP4

The NM_001080483.3(MYMK):c.271C>A(p.Pro91Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,944 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: MYMK NM_001080483.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:2
• Conservation: PhyloP100: 9.28

Genes affected

MYMK (HGNC:33778): (myomaker, myoblast fusion factor) Involved in myoblast fusion. Located in plasma membrane. Implicated in Carey-Fineman-Ziter syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Protein myomaker (size 220) in uniprot entity MYMK_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_001080483.3
• PP5: Variant 9-133519002-G-T is Pathogenic according to our data. Variant chr9-133519002-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133519002-G-T is described in Lovd as [Pathogenic]. Variant chr9-133519002-G-T is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.02295518).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYMK	NM_001080483.3	c.271C>A	p.Pro91Thr	missense_variant	3/5	ENST00000339996.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYMK	ENST00000339996.4	c.271C>A	p.Pro91Thr	missense_variant	3/5	2	NM_001080483.3	P1
MYMK	ENST00000413714.1	n.326C>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 189 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00124 AC: 311 AN: 250752 Hom.: 0 AF XY: 0.00122 AC XY: 165 AN XY: 135548

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00199 AC: 2905 AN: 1461660 Hom.: 2 Cov.: 31 AF XY: 0.00196 AC XY: 1425 AN XY: 727108

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000556

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.00243

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00124 AC: 189 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74458

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00207

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00169 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00128 AC: 155

EpiCase AF: 0.00218

EpiControl AF: 0.00207

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital nonprogressive myopathy with Moebius and Robin sequences Pathogenic:5 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 02, 2022	Variant summary: MYMK c.271C>A (p.Pro91Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 282106 control chromosomes, found exclusively in the heterozygous state, and predominantly at a frequency of 0.0022 within the Non-Finnish European subpopulation in the gnomAD database. c.271C>A has been reported in the literature in the compound heterozygous state in at least 10 individuals affected with Congenital Nonprogressive Myopathy With Moebius And Robin Sequences (Carey-Fineman-Ziter Syndrome) from 5 different families in which the variant segregrated with the disease phenotype (e.g. Di Gioia_2017, Hedberg-Oldfors_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Di Gioia_2017). These results indicated that the variant results in a partial loss of function, as observed in a zebrafish model, and has reduced protein expression in in vitro experiments but retains residual function upon overexpression. As a result of these experimental findings, it has been proposed that c.271C>A is likely a hypomorphic variant. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority have classified the variant as either pathogenic (n=4) or likely pathogenic (n=2), and the remaining have classified it as VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The heterozygous p.Pro91Thr variant in TMEM8C was identified by our study in the compound heterozygous state, with a VUS, in one individual with Carey-Finteman-Ziter syndrome. This variant has been identified in 0.1186% (328/276516) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137868995). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The p.Pro91Thr variant in MYMK has been reported in 7 Caucasian individuals from the US and New Zealand with Carey Finteman-Ziter syndrome and segregated with disease in 6 affected relatives from 3 families (PMID: 28681861). The presence of this variant in combination with 3 variants reported pathogenic by OMIM in ClinVar and in 7 individuals with Carey-Finteman-Ziter syndrome increases the likelihood that the p.Pro91Thr variant is pathogenic. In vitro functional studies provide some evidence that the p.Pro91Thr variant may impact, but not eliminate, myoblast fusion activity (PMID: 28681861). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP1, PS3_Supporting (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 05, 2019	The MYMK c.271C>A (p.Pro91Thr) variant is a missense variant that has been reported in three studies and is found in a total of 11 individuals from six families with phenotypes overlapping Carey-Fineman-Ziter syndrome, all carrying the variant in a compound heterozygous state with a second missense variant (Di Gioia et al. 2017; Alrohaif et al. 2018; Hedberg-Oldfors et al. 2018). Individuals ranged in age from one to 69 years and the main phenotypes included facial muscle weakness, motor delays, generalized muscle hypoplasia, congenital contractures, hypermobility, myopathy noted through electromyography, growth failure, feeding problems, skeletal features including scoliosis and short stature, and facial and head features including broad nasal tip, micrognathia or retrognathia, lagophthalmos, ptosis, high palate, cleft palate, and a thin tubular neck. Parents were also genotyped in five of the families, showing an unaffected parent carrying the variant in a heterozygous state (Di Gioia et al. 2017; Hedberg-Oldfors et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.002192 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies showed an effect on protein stability in HeLa cells and lower expression levels in C2C12 cells with FLAG-tagged human p.Pro91Thr constructs. However, presence of this variant did not affect myoblast fusion. In zebrafish studies, the p.Pro91Thr variant partially rescued the phenotype, whereas there was complete rescue with wild-type mRNA (Di Gioia et al. 2017). Based on the collective evidence, the p.Pro91Thr variant is classified as pathogenic for Carey-Fineman-Ziter syndrome. -
Uncertain significance, flagged submission	clinical testing	Baylor Genetics	Jul 18, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Carey-Fineman-Ziter syndrome (MIM#254940). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (341 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and very high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously reported in many individuals with Carey-Fineman-Ziter syndrome (MIM#254940) (ClinVar, PMID: 28681861, 29560417). (SP) 0901 - This variant has strong evidence for segregation with disease. The variant has been reported to segregate with disease in at least five families (PMID: 28681861, PMID: 30065953) (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. The variant is considered to be hypomorphic as it results in a partial loss of function rather than a null allele (PMID: 28681861). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Carey-Fineman-Ziter syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 20, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 30, 2020	This sequence change is predicted to replace proline with threonine at codon 91 of the MYMK protein (p.(Pro91Thr)). The proline residue is invariant across species (100 vertebrates, UCSC), and is located in a domain of unknown function. There is a small physicochemical difference between proline and threonine. The variant is present in a large population cohort at a frequency of 0.1% (rs137868995, 341/282,106 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified with a second allele in at least six individuals with congenital nonprogressive myopathy with Moebius and Robin sequences, and segregates in affected siblings in multiple families (PMID: 28681861, 29560417, 30065953). The variant is a hypomorph, and the fusogenic activity of the mutant protein is fully/partially rescued in a zebrafish model (PMID: 28681861). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PP1_Strong, PS3_Supporting. -

MYMK-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 18, 2023

The MYMK c.271C>A variant is predicted to result in the amino acid substitution p.Pro91Thr. This variant has been reported in the compound heterozygous state in multiple individuals with Carey-Fineman-Ziter syndrome (Figure S1, Di Gioia et al. 2017. PubMed ID: 28681861; Alrohaif et al. 2018. PubMed ID: 29560417; Hedberg-Oldfors et al. 2018. PubMed ID: 30065953). This variant is reported in 0.22% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided Uncertain:1

Uncertain significance, flagged submission

clinical testing

GeneDx

Apr 03, 2023

In silico analysis supports that this missense variant does not alter protein structure/function, and published functional studies suggest residual protein activity is more similar to wild type activity than to null allele activity (Di Gioia et al., 2017); This variant is associated with the following publications: (PMID: 7131178, 28681861, 30065953, 29560417, 32573669, 32333597, 32528171) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.31	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.39
MPC		1.1
ClinPred		0.066	T
GERP RS		5.1
Varity_R		0.18
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137868995; hg19: chr9-136384124;