chr19-50252727-G-A

Position:

• chr19-50252727-G-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.1919G>A​(p.Arg640Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 1,595,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R640W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.10

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=0.01598835).
• BP6: Variant 19-50252727-G-A is Benign according to our data. Variant chr19-50252727-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr19-50252727-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000506 (77/152246) while in subpopulation AMR AF= 0.00085 (13/15292). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 77 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1919G>A	p.Arg640Gln	missense_variant	16/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1919G>A	p.Arg640Gln	missense_variant	16/42		NP_001070654.1
MYH14	NM_024729.4	c.1895G>A	p.Arg632Gln	missense_variant	15/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1919G>A	p.Arg640Gln	missense_variant	16/43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000677 AC: 148 AN: 218616 Hom.: 0 AF XY: 0.000763 AC XY: 90 AN XY: 118008

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00285

Gnomad EAS exome AF: 0.000315

Gnomad SAS exome AF: 0.000485

Gnomad FIN exome AF: 0.0000511

Gnomad NFE exome AF: 0.000921

Gnomad OTH exome AF: 0.000544

GnomAD4 exome AF: 0.000515 AC: 744 AN: 1443320 Hom.: 0 Cov.: 30 AF XY: 0.000545 AC XY: 390 AN XY: 716220

Gnomad4 AFR exome AF: 0.0000607

Gnomad4 AMR exome AF: 0.000214

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.000440

Gnomad4 SAS exome AF: 0.000469

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.000515

Gnomad4 OTH exome AF: 0.000435

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74442

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000618

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000929 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000603 AC: 73

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MYH14: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2020	This variant is associated with the following publications: (PMID: 23804846) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 30, 2014

Variant classified as Uncertain Significance - Favor Benign. The p.Arg640Gln var iant in MYH14 has not been previously reported in individuals with hearing loss. This variant has been identified in 0.2% (52/26604) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 199696801). Although this variant has been seen in the general population, its f requency is not high enough to rule out a pathogenic role. Computational predict ion tools and conservation analyses suggest that the Arg640Gln variant may not i mpact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg640Gln va riant is uncertain, these data suggest that it is more likely to be benign. -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

MYH14-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2021

This variant is classified as likely 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	Benign	0.087
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;.;T;.;T;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.93	.;D;D;.;D;D;.
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.016	T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.29	.;.;N;.;.;.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.69	.;N;N;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.15	.;T;T;.;.;.;.
Sift4G	Benign	0.31	T;T;T;.;T;T;T
Polyphen		0.087	B;B;B;B;.;B;B
Vest4		0.37
MVP		0.75
MPC		0.53
ClinPred		0.020	T
GERP RS		2.2
Varity_R		0.049
gMVP		0.35

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: rs199696801; hg19: chr19-50755984; COSMIC: COSV51814892; COSMIC: COSV51814892;