rs374883445

Positions:

• chr19-50268174-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001145809.2(MYH14):​c.2840G>A​(p.Arg947His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,546,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R947R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.33

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2121031).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000164 (25/152308) while in subpopulation AFR AF= 0.000529 (22/41572). AF 95% confidence interval is 0.000358. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.2840G>A	p.Arg947His	missense_variant	24/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.2741G>A	p.Arg914His	missense_variant	23/42		NP_001070654.1
MYH14	NM_024729.4	c.2717G>A	p.Arg906His	missense_variant	22/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.2840G>A	p.Arg947His	missense_variant	24/43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000131 AC: 20 AN: 152494 Hom.: 0 AF XY: 0.000111 AC XY: 9 AN XY: 81058

Gnomad AFR exome AF: 0.000996

Gnomad AMR exome AF: 0.000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.0000337 AC: 47 AN: 1394516 Hom.: 0 Cov.: 34 AF XY: 0.0000320 AC XY: 22 AN XY: 687882

Gnomad4 AFR exome AF: 0.000475

Gnomad4 AMR exome AF: 0.000391

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74486

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000185

ESP6500AA AF: 0.000733 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000282 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 18, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH14 protein function. ClinVar contains an entry for this variant (Variation ID: 164181). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. This variant is present in population databases (rs374883445, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 906 of the MYH14 protein (p.Arg906His). -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 20, 2014

The Arg947His in MYH14 has not been reported in individuals with hearing loss, b ut has been identified in 0.07% (3/4092) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu). The arginine (Arg ) at position 947 is conserved in mammals, but not in evolutionarily distant spe cies. This raises the possibility that a change at this position may be tolerate d. Other computational prediction tools suggest that the Arg947His variant may i mpact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the Arg947His variant i s uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	.;.;D;.;D;.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.26	N
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;.
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Uncertain	2.0	.;.;M;.;.;.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.4	.;D;.;.;.;.;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	.;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.25
MVP		0.74
MPC		1.4
ClinPred		0.14	T
GERP RS		3.9
Varity_R		0.045
gMVP		0.30

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: rs374883445; hg19: chr19-50771431; COSMIC: COSV51810673; COSMIC: COSV51810673;