rs119103280

Positions:

• chr19-50244277-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.1150G>T​(p.Gly384Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,613,848 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (22 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:12
• Conservation: PhyloP100: 9.88

Genes affected

MYH14 (HGNC:23212): (myosin heavy chain 14) This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.06556776).
• BP6: Variant 19-50244277-G-T is Benign according to our data. Variant chr19-50244277-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2199.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=2}. Variant chr19-50244277-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.003 (457/152178) while in subpopulation NFE AF= 0.00434 (295/68008). AF 95% confidence interval is 0.00393. There are 0 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 457 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1150G>T	p.Gly384Cys	missense_variant	11/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1150G>T	p.Gly384Cys	missense_variant	11/42		NP_001070654.1
MYH14	NM_024729.4	c.1126G>T	p.Gly376Cys	missense_variant	10/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1150G>T	p.Gly384Cys	missense_variant	11/43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 457 AN: 152060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00304 AC: 757 AN: 248750 Hom.: 5 AF XY: 0.00321 AC XY: 434 AN XY: 135002

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00413

GnomAD4 exome AF: 0.00382 AC: 5578 AN: 1461670 Hom.: 22 Cov.: 32 AF XY: 0.00380 AC XY: 2761 AN XY: 727118

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00418

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.00277 AC XY: 206 AN XY: 74386

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00434

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00433 Hom.: 3

Bravo AF: 0.00301

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000702 AC: 3

ESP6500EA AF: 0.00389 AC: 33

ExAC AF: 0.00285 AC: 345

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00557

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:8

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2020	This variant is associated with the following publications: (PMID: 27391121, 25262649, 30622556, 15015131, 27884173, 25098841, 30245029, 31898538) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	MYH14: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 05, 2017	p.Gly384Cys in exon 11 of MYH14: This variant is not expected to have clinical s ignificance, because it has been identified in 1.3% (136/10142) of Ashkenazi Jew ish chromosomes including 1 homozygote by the Genome Aggregation Database (gnomA D, http://gnomad.broadinstitute.org/; dbSNP rs119103280). Although this variant has been reported as a de novo variant in one individual with moderate sensorine ural hearing loss (Donaudy 2004), the evidence is not sufficient to establish ca usality. -

Autosomal dominant nonsyndromic hearing loss 4A Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

European Non-Finnish population allele frequency is 0.3994% (rs119103280, 511/127.956 alleles, 1 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;D;.;D
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.066	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	4.2	.;.;H;.;.;.;H
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.9	.;D;D;.;.;.;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.91
MVP		0.97
MPC		1.4
ClinPred		0.12	T
GERP RS		3.4
Varity_R		0.61
gMVP		0.87

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: rs119103280; hg19: chr19-50747534;