NM_001145809.2:c.2600G>A

Variant names:

• chr19-50263326-G-A
• rs547836952
• NM_001145809.2:c.2600G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):​c.2600G>A​(p.Arg867His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000499 in 1,562,446 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.88

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010991424).
• BP6: Variant 19-50263326-G-A is Benign according to our data. Variant chr19-50263326-G-A is described in ClinVar as [Benign]. Clinvar id is 329922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50263326-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000387 (59/152306) while in subpopulation SAS AF= 0.00996 (48/4818). AF 95% confidence interval is 0.00772. There are 1 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 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2600G>A	p.Arg867His	missense_variant	Exon 22 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2501G>A	p.Arg834His	missense_variant	Exon 21 of 42		NP_001070654.1
MYH14	NM_024729.4	c.2477G>A	p.Arg826His	missense_variant	Exon 20 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2600G>A	p.Arg867His	missense_variant	Exon 22 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00106 AC: 192 AN: 180606 Hom.: 2 AF XY: 0.00140 AC XY: 136 AN XY: 97102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.000342

Gnomad EAS exome AF: 0.000155

Gnomad SAS exome AF: 0.00743

Gnomad FIN exome AF: 0.000113

Gnomad NFE exome AF: 0.0000520

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.000511 AC: 721 AN: 1410140 Hom.: 7 Cov.: 30 AF XY: 0.000714 AC XY: 498 AN XY: 697200

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000159

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.00807

Gnomad4 FIN exome AF: 0.000140

Gnomad4 NFE exome AF: 0.0000304

Gnomad4 OTH exome AF: 0.000360

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74468

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00996

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00106 AC: 127

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 11, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Arg867His in exon 22 of MYH14: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (177/23764) of South Asian ch romosomes including 2 homozygotes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org; dbSNP rs547836952). -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	.;.;D;.;T;.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.61	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;.
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.043	D
MutationAssessor	Uncertain	2.2	.;.;M;.;.;.;M
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;.;.;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	.;D;.;.;.;.;.
Sift4G	Uncertain	0.045	D;D;D;.;T;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.42
MVP		0.82
MPC		1.5
ClinPred		0.086	T
GERP RS		3.0
Varity_R		0.069
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs547836952; hg19: chr19-50766583;