19-50249039-G-T

Position:

• chr19-50249039-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001145809.2(MYH14):​c.1382G>T​(p.Arg461Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,613,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.83

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.

• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1382G>T	p.Arg461Leu	missense_variant	13/43	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1382G>T	p.Arg461Leu	missense_variant	13/42		NP_001070654.1
MYH14	NM_024729.4	c.1358G>T	p.Arg453Leu	missense_variant	12/41		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1382G>T	p.Arg461Leu	missense_variant	13/43		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152258 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 246016 Hom.: 0 AF XY: 0.0000299 AC XY: 4 AN XY: 133930

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000660

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460918 Hom.: 0 Cov.: 32 AF XY: 0.0000716 AC XY: 52 AN XY: 726672

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000882

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

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: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000780 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000237 AC: 2

ExAC AF: 0.0000165 AC: 2

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 provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This sequence change replaces arginine with leucine at codon 453 of the MYH14 protein (p.Arg453Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs370353590, ExAC 0.007%). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2021	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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	.;.;D;.;D;.;D
Eigen	Benign	-0.038
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;.;D;D;.
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.095	.;.;N;.;.;.;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.1	.;D;D;.;.;.;.
REVEL	Uncertain	0.56
Sift	Benign	0.088	.;T;T;.;.;.;.
Sift4G	Benign	0.16	T;T;T;.;T;T;T
Polyphen		0.036	B;B;B;B;.;B;B
Vest4		0.76
MVP		0.94
MPC		0.67
ClinPred		0.38	T
GERP RS		4.2
Varity_R		0.50
gMVP		0.61

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: rs370353590; hg19: chr19-50752296;