19-50272586-C-T

Variant names:

• chr19-50272586-C-T
• rs769702697
• NM_001145809.2:c.3322C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001145809.2(MYH14):​c.3322C>T​(p.Arg1108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,578,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.18

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 Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.3322C>T	p.Arg1108Cys	missense_variant	Exon 27 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.3223C>T	p.Arg1075Cys	missense_variant	Exon 26 of 42		NP_001070654.1
MYH14	NM_024729.4	c.3199C>T	p.Arg1067Cys	missense_variant	Exon 25 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.3322C>T	p.Arg1108Cys	missense_variant	Exon 27 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000206 AC: 4 AN: 193832 Hom.: 0 AF XY: 0.0000192 AC XY: 2 AN XY: 104110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000687

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000154 AC: 22 AN: 1426554 Hom.: 0 Cov.: 32 AF XY: 0.0000142 AC XY: 10 AN XY: 706046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000258

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000783

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000164

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

May 13, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg1108Cys variant in MYH14 has not been previously reported in individual s with hearing loss. Data from large population studies are insufficient to asse ss the frequency of this variant in the general population. Computational predic tion tools and conservation analyses suggest that this variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, the clinical significance of the p.Arg1108Cys variant is uncerta in. -

not provided Uncertain:1

Oct 19, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.;.;D;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;D;.;D;.;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Pathogenic	3.1	.;.;M;.;.;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.6	.;D;.;.;.;.;D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	.;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.
Vest4		0.72
MutPred		0.50		.;.;Loss of MoRF binding (P = 0.0261);.;.;Loss of MoRF binding (P = 0.0261);.;
MVP		0.86
MPC		0.77
ClinPred		0.91	D
GERP RS		3.1
Varity_R		0.17
gMVP		0.54

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: rs769702697; hg19: chr19-50775843; COSMIC: COSV104572839; COSMIC: COSV104572839;