rs138001307

chr19-50217735-G-Achr19-50217735-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001145809.2(MYH14):c.526G>A(p.Ala176Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000208 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A176V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 4.76

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 -9 ACMG points.

• BP6: Variant 19-50217735-G-A is Benign according to our data. Variant chr19-50217735-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228878.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000216 (315/1461576) while in subpopulation MID AF= 0.000693 (4/5768). AF 95% confidence interval is 0.000236. There are 0 homozygotes in gnomad4_exome. There are 154 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH14	NM_001145809.2	c.526G>A	p.Ala176Thr	missense_variant	3/43	ENST00000642316.2
MYH14	NM_001077186.2	c.526G>A	p.Ala176Thr	missense_variant	3/42
MYH14	NM_024729.4	c.526G>A	p.Ala176Thr	missense_variant	3/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH14	ENST00000642316.2	c.526G>A	p.Ala176Thr	missense_variant	3/43		NM_001145809.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 43 AN: 248994 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135098

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461576 Hom.: 0 Cov.: 33 AF XY: 0.000212 AC XY: 154 AN XY: 727082

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74494

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000297 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.000182 AC: 22

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2020	This variant is associated with the following publications: (PMID: 27610647) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Apr 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2017	The p.Ala176Thr variant has not been reported in the medical literature, and is not listed in gene-specific variant databases. It has been previously identified in our laboratory in an individual with suspected sensorineural hearing loss. The p.Ala176Thr variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.028% in the non-Finnish European population (identified in 31 out of 111,448 chromosomes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 228878). The alanine at codon 176 is highly conserved considering 7 species up to cow (Alamut software v2.9.0), and computational analyses suggest that this variant affects the MYH14 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available information, the clinical significance of the p.Ala176Thr variant cannot be determined with certainty. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 01, 2015	The p.Ala176Thr variant in MYH14 has not been previously reported in individuals with hearing loss. This variant has been identified in 0.03% 18/67222 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs138001307). Although this variant has been seen in the general p opulation, its frequency is not high enough to rule out a pathogenic role. Compu tational prediction tools and conservation analyses suggest that the p.Ala176Thr variant may impact the protein, though this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the p.Ala 176Thr variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2024	Variant summary: Variant summary: The CBS c.526G>A (p.Glu176Lys) variant located in the pyridoxal-phosphate dependent enzyme domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. Multiple functional studies, Janocik_2001, Lu_2012, and Hnizda_2012, support these predictions with observations that the variant impedes proper CBS protein function. This variant is absent in 184408 control chromosomes (gnomAD). Multiple publications have cited the variant in a homozygous and compound heterozygote patients. However, to our knowledge, the variant of interest has not been citied by reputable clinical diagnostic laboratories. Taken together, this variant is classified as pathogenic. -

Autosomal dominant nonsyndromic hearing loss 4A Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	research	Miami Human Genetics, University Of Miami Miller School Of Medicine	Jun 02, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.9	M;M;M;M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.028	D;D;D;.;D;D;D
Polyphen		1.0	D;D;D;D;.;D;D
Vest4		0.85
MVP		0.84
MPC		1.3
ClinPred		0.42	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.74

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: rs138001307; hg19: chr19-50720992; COSMIC: COSV51809835;