rs727503225

chr19-50280352-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001145809.2(MYH14):c.4259C>T(p.Ala1420Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,546,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1420A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.170

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05962336).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.4259C>T	p.Ala1420Val	missense_variant	32/43	ENST00000642316.2
MYH14	NM_001077186.2	c.4160C>T	p.Ala1387Val	missense_variant	31/42
MYH14	NM_024729.4	c.4136C>T	p.Ala1379Val	missense_variant	30/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.4259C>T	p.Ala1420Val	missense_variant	32/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

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: 0.0000593 AC: 9 AN: 151730 Hom.: 0 AF XY: 0.0000621 AC XY: 5 AN XY: 80492

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000923

Gnomad SAS exome AF: 0.0000446

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000513

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000989 AC: 138 AN: 1394786 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 77 AN XY: 687546

Gnomad4 AFR exome AF: 0.0000635

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000841

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000332 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1379 of the MYH14 protein (p.Ala1379Val). This variant is present in population databases (rs727503225, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYH14-related conditions. ClinVar contains an entry for this variant (Variation ID: 164191). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYH14 protein function. 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. -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2024	Variant summary: MYH14 c.4136C>T (p.Ala1379Val) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 1,541,506 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation (i.e. 123 carriers) in the gnomAD database (v4 dataset). The high number of carriers suggests that this variant is unlikely to be associated with an early onset, severe, high penetrance disease phenotype. To our knowledge, no occurrence of c.4136C>T in individuals affected with Deafness, Autosomal Dominant 4 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 164191). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2013	Variant classified as Uncertain Significance - Favor Benign. The Ala1420Val vari ant in MYH14 has not been previously reported in individuals with hearing loss a nd data from large population studies is insufficient to determine its frequency . The amino acid residue at this position is not well conserved with several spe cies, including mammals, having this variant (Val) at this position. Computatio nal analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPh en2, and SIFT) do not suggest an impact to the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical sig nificance of this variant cannot be determined with certainty; however, based up on the arguments described above, we would lean towards a more likely benign rol e. -

Autosomal dominant nonsyndromic hearing loss 4A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0053	N
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.060	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.66	T
Sift4G	Benign	0.28	T;T;T;T;.;T;T;T
Polyphen		0.024	B;.;B;B;B;B;B;.
Vest4		0.12
MVP		0.27
MPC		0.15
ClinPred		0.015	T
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.15

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: rs727503225; hg19: chr19-50783609;