rs367560074

Variant names:

• chr19-50244349-G-A
• rs367560074
• NM_001145809.2:c.1210+12G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50244349-G-A
• chr19-50244349-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001145809.2(MYH14):​c.1210+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,611,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.91
• Publications: 0 publications found

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]

MYH14 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 4A

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-50244349-G-A is Benign according to our data. Variant chr19-50244349-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504616.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000158 (24/151892) while in subpopulation NFE AF = 0.00025 (17/67988). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.1210+12G>A		intron_variant	Intron 11 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.1210+12G>A		intron_variant	Intron 11 of 41		NP_001070654.1
MYH14	NM_024729.4	c.1186+12G>A		intron_variant	Intron 10 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.1210+12G>A		intron_variant	Intron 11 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151892 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000250

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000127 AC: 31 AN: 243396 AF XY: 0.000136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 254 AN: 1459648 Hom.: 0 Cov.: 31 AF XY: 0.000167 AC XY: 121 AN XY: 726150

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.0000894 AC: 4 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000212 AC: 236 AN: 1111128

Other (OTH) AF: 0.000116 AC: 7 AN: 60328

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151892 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74158

African (AFR) AF: 0.0000726 AC: 3 AN: 41338

American (AMR) AF: 0.000131 AC: 2 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67988

Other (OTH) AF: 0.000961 AC: 2 AN: 2082

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000268

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 4A Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:1

Jun 06, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1210+12G>A in Intron 11 of MYH14: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 34/122731 European chromosomes by the Genome A ggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs367560074 ). -

not provided Benign:1

Mar 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.066
DANN	Benign	0.82
PhyloP100		-1.9

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

Other links and lift over

dbSNP: rs367560074; hg19: chr19-50747606;