19-50301790-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001145809.2(MYH14):c.5599C>T(p.Arg1867Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000695 in 1,612,504 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.70

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09227243).
• BP6: Variant 19-50301790-C-T is Benign according to our data. Variant chr19-50301790-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329949.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000723 (11/152194) while in subpopulation EAS AF= 0.00194 (10/5166). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.5599C>T	p.Arg1867Cys	missense_variant	40/43	ENST00000642316.2
MYH14	NM_001077186.2	c.5500C>T	p.Arg1834Cys	missense_variant	39/42
MYH14	NM_024729.4	c.5476C>T	p.Arg1826Cys	missense_variant	38/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.5599C>T	p.Arg1867Cys	missense_variant	40/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 48 AN: 245670 Hom.: 0 AF XY: 0.000180 AC XY: 24 AN XY: 133664

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00240

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000503

GnomAD4 exome AF: 0.0000692 AC: 101 AN: 1460310 Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48 AN XY: 726408

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74418

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	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; This variant is associated with the following publications: (PMID: 33229591) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2016

The p.Arg1867Cys variant in MYH14 has not been previously reported in individual s with hearing loss, but has been identified in 0.2% (15/8434) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs187789045). Although this variant has been seen in the general popul ation, its frequency is not high enough to rule out a pathogenic role. Computati onal prediction tools and conservation analysis suggest that the p.Arg1867Cys va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, the clinical significance of the p.Arg186 7Cys variant is uncertain. -

Autosomal dominant nonsyndromic hearing loss 4A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.092	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.0062	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.014	D;D;D;D;.;D;D
Polyphen		1.0	D;.;D;D;D;D;D
Vest4		0.33
MVP		0.79
MPC		0.75
ClinPred		0.20	T
GERP RS		0.25
Varity_R		0.17
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs187789045; hg19: chr19-50805047; COSMIC: COSV51818905;