rs35315400

chr19-50231990-C-Gchr19-50231990-C-T

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.1034C>G(p.Ser345Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,954 control chromosomes in the GnomAD database, including 3 homozygotes. 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).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.18

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=0.008297592).
• BP6: Variant 19-50231990-C-G is Benign according to our data. Variant chr19-50231990-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178414.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00224 (341/152394) while in subpopulation AFR AF= 0.00798 (332/41596). AF 95% confidence interval is 0.00727. There are 2 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.1034C>G	p.Ser345Cys	missense_variant	10/43	ENST00000642316.2
MYH14	NM_001077186.2	c.1034C>G	p.Ser345Cys	missense_variant	10/42
MYH14	NM_024729.4	c.1010C>G	p.Ser337Cys	missense_variant	9/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.1034C>G	p.Ser345Cys	missense_variant	10/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152276 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00798

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

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: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000590 AC: 147 AN: 248998 Hom.: 2 AF XY: 0.000429 AC XY: 58 AN XY: 135128

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.000203

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: 0.000165

GnomAD4 exome AF: 0.000203 AC: 297 AN: 1461560 Hom.: 1 Cov.: 31 AF XY: 0.000168 AC XY: 122 AN XY: 727058

Gnomad4 AFR exome AF: 0.00747

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152394 Hom.: 2 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74530

Gnomad4 AFR AF: 0.00798

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.00249

ESP6500AA AF: 0.00912 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000794 AC: 96

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 29, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.1010C>G (p.S337C) alteration is located in exon 9 (coding exon 8) of the MYH14 gene. This alteration results from a C to G substitution at nucleotide position 1010, causing the serine (S) at amino acid position 337 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Ser345Cys in Exon 10 of MYH14: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (30/3264) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35315400). -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2019

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	Benign	0.066
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0083	T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.40	T
Sift4G	Uncertain	0.0090	D;D;D;.;D;D;D
Polyphen		0.99	D;D;D;D;.;D;D
Vest4		0.35
MVP		0.52
MPC		0.72
ClinPred		0.041	T
GERP RS		3.0
Varity_R		0.19
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: rs35315400; hg19: chr19-50735247;