rs556541366

chr19-50247094-A-Gchr19-50247094-A-T

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.1301A>G(p.Tyr434Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,613,440 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (1 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.85

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=0.019899458).
• BP6: Variant 19-50247094-A-G is Benign according to our data. Variant chr19-50247094-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 179004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000138 (21/152242) while in subpopulation EAS AF= 0.00367 (19/5184). AF 95% confidence interval is 0.0024. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.1301A>G	p.Tyr434Cys	missense_variant	12/43	ENST00000642316.2
MYH14	NM_001077186.2	c.1301A>G	p.Tyr434Cys	missense_variant	12/42
MYH14	NM_024729.4	c.1277A>G	p.Tyr426Cys	missense_variant	11/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.1301A>G	p.Tyr434Cys	missense_variant	12/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000254 AC: 63 AN: 247914 Hom.: 0 AF XY: 0.000230 AC XY: 31 AN XY: 134592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00338

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461198 Hom.: 1 Cov.: 30 AF XY: 0.0000578 AC XY: 42 AN XY: 726788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00207

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000297 AC: 36

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 05, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 04, 2015

p.Tyr434Cys in exon 12 of MYH14: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (36/8364) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs556541366). -

Autosomal dominant nonsyndromic hearing loss 4A;C3280556:Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.075
Eigen_PC	Benign	0.091
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.020	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.041	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
Sift4G	Uncertain	0.010	D;D;D;.;D;D;D
Polyphen		0.42	B;B;P;B;.;B;P
Vest4		0.76
MutPred		0.48		.;.;Gain of ubiquitination at K429 (P = 0.0726);.;.;.;Gain of ubiquitination at K429 (P = 0.0726);
MVP		0.74
MPC		1.4
ClinPred		0.18	T
GERP RS		2.6
Varity_R		0.29
gMVP		0.56

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: rs556541366; hg19: chr19-50750351;