rs141995460

Positions:

• chr19-50281789-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001145809.2(MYH14):​c.4486C>G​(p.Gln1496Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,612,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.68

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17031577).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4486C>G	p.Gln1496Glu	missense_variant	33/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4387C>G	p.Gln1463Glu	missense_variant	32/42
MYH14	NM_024729.4	c.4363C>G	p.Gln1455Glu	missense_variant	31/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4486C>G	p.Gln1496Glu	missense_variant	33/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000289 AC: 7 AN: 242458 Hom.: 0 AF XY: 0.0000301 AC XY: 4 AN XY: 132922

Gnomad AFR exome AF: 0.0000693

Gnomad AMR exome AF: 0.000116

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: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460320 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726444

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152368 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74514

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000249 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 05, 2014

The Gln1496Glu variant in MYH14 has not been previously reported in individuals with hearing loss, but it has been identified in 0.52% (1/192) of Luhya (Kenya) chromosomes by the 1000 Genomes Project (dbSNP rs141995460). Although this varia nt has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal yses suggest that the Gln1496Glu variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the Gln1496Glu variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The c.4363C>G (p.Q1455E) alteration is located in exon 31 (coding exon 30) of the MYH14 gene. This alteration results from a C to G substitution at nucleotide position 4363, causing the glutamine (Q) at amino acid position 1455 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Benign	0.96
Eigen	Benign	0.010
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.17	T;T;T;T;.;T;T;T
Polyphen		0.41	B;.;B;P;P;P;P;.
Vest4		0.28
MVP		0.59
MPC		0.28
ClinPred		0.088	T
GERP RS		4.0
Varity_R		0.22
gMVP		0.11

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: rs141995460; hg19: chr19-50785046;