NM_001145809.2:c.5446C>T

Variant names:

• chr19-50293664-C-T
• rs376798395
• NM_001145809.2:c.5446C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BS1_Supporting BS2

The NM_001145809.2(MYH14):​c.5446C>T​(p.Arg1816Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000627 in 1,594,100 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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 -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000659 (95/1441802) while in subpopulation NFE AF= 0.0000817 (90/1101192). AF 95% confidence interval is 0.0000676. There are 0 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 47. 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 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.5446C>T	p.Arg1816Cys	missense_variant	Exon 39 of 43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.5347C>T	p.Arg1783Cys	missense_variant	Exon 38 of 42		NP_001070654.1
MYH14	NM_024729.4	c.5323C>T	p.Arg1775Cys	missense_variant	Exon 37 of 41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.5446C>T	p.Arg1816Cys	missense_variant	Exon 39 of 43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.00000853 AC: 2 AN: 234406 Hom.: 0 AF XY: 0.00000790 AC XY: 1 AN XY: 126588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000312

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: 0.00000939

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000659 AC: 95 AN: 1441802 Hom.: 0 Cov.: 47 AF XY: 0.0000629 AC XY: 45 AN XY: 715298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000817

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 04, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg1816Cys variant in MYH14 has not been previously reported in individuals with hearing loss, but has been identified in 1/8586 European American chromosom es by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). Com putational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the cl inical significance of the Arg1816Cys variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	.;.;.;D;.;.;D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	1.0	.;D;D;D;.;D;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	.;.;.;M;.;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;.;.;.
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;D
Polyphen		1.0	D;.;D;D;D;D;D
Vest4		0.57
MVP		0.77
MPC		0.74
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.21
gMVP		0.40

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: rs376798395; hg19: chr19-50796921; COSMIC: COSV99221616;