9-133518908-A-G

Position:

• chr9-133518908-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001080483.3(MYMK):​c.365T>C​(p.Ile122Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYMK NM_001080483.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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]

MYMK (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain Protein myomaker (size 220) in uniprot entity MYMK_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001080483.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYMK	NM_001080483.3	c.365T>C	p.Ile122Thr	missense_variant	3/5	ENST00000339996.4	NP_001073952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYMK	ENST00000339996.4	c.365T>C	p.Ile122Thr	missense_variant	3/5	2	NM_001080483.3	ENSP00000419712.2
MYMK	ENST00000413714.1	n.420T>C		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461320 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.61	T
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.28
Sift	Benign	0.21	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.87
MutPred		0.53		Loss of catalytic residue at L127 (P = 0.0527);
MVP		0.70
MPC		0.64
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.80

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: rs1389031848; hg19: chr9-136384030;