rs397516628

Variant names:

• chr19-50260650-G-A
• rs397516628
• NM_001145809.2:c.2359G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.2359G>A​(p.Glu787Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000866 in 1,612,592 control chromosomes in the GnomAD database, including 15 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 0.00057 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00090 (15 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 9.70

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011690229).
• BP6: Variant 19-50260650-G-A is Benign according to our data. Variant chr19-50260650-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44058.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000566 (86/151920) while in subpopulation SAS AF= 0.0169 (81/4786). AF 95% confidence interval is 0.014. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2359G>A	p.Glu787Lys	missense_variant	Exon 20 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2260G>A	p.Glu754Lys	missense_variant	Exon 19 of 42		NP_001070654.1
MYH14	NM_024729.4	c.2236G>A	p.Glu746Lys	missense_variant	Exon 18 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2359G>A	p.Glu787Lys	missense_variant	Exon 20 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.000567 AC: 86 AN: 151800 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0169

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00178 AC: 442 AN: 248792 Hom.: 2 AF XY: 0.00237 AC XY: 320 AN XY: 135106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0143

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000897 AC: 1310 AN: 1460672 Hom.: 15 Cov.: 33 AF XY: 0.00128 AC XY: 932 AN XY: 726674

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0142

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000566 AC: 86 AN: 151920 Hom.: 0 Cov.: 30 AF XY: 0.000862 AC XY: 64 AN XY: 74248

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.0169

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000464 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Aug 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH14: BS1 -

not specified Uncertain:1

Feb 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Glu787Lys variant in MYH14 has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stro ng support for or against an impact to the protein. Additional data is needed to determine the clinical significance of this variant. -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

MYH14-related disorder Benign:1

Dec 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;.;D;.;D;.;D
Eigen	Benign	0.093
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;.
MetaRNN	Benign	0.012	T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.1	.;.;L;.;.;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	.;D;.;.;.;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	.;D;.;.;.;.;.
Sift4G	Benign	0.14	T;T;T;.;T;T;T
Polyphen		0.88	P;P;P;P;.;P;P
Vest4		0.82
MutPred		0.51		.;.;Gain of MoRF binding (P = 0.0091);.;.;.;Gain of MoRF binding (P = 0.0091);
MVP		0.87
MPC		0.93
ClinPred		0.16	T
GERP RS		4.2
Varity_R		0.28
gMVP		0.78

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: rs397516628; hg19: chr19-50763907; COSMIC: COSV105861926; COSMIC: COSV105861926;