chr19-50281852-C-T

Variant names:

• chr19-50281852-C-T
• rs561531825
• NM_001145809.2:c.4539+10C>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.4539+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000486 in 1,605,864 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 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.01
• 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=-0.49).
• BP6: Variant 19-50281852-C-T is Benign according to our data. Variant chr19-50281852-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 164195.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000525 (8/152362) while in subpopulation SAS AF = 0.000621 (3/4830). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.4539+10C>T		intron_variant	Intron 33 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.4440+10C>T		intron_variant	Intron 32 of 41		NP_001070654.1
MYH14	NM_024729.4	c.4416+10C>T		intron_variant	Intron 31 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.4539+10C>T		intron_variant	Intron 33 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000832 AC: 20 AN: 240434 AF XY: 0.0000455

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.0000482 AC: 70 AN: 1453502 Hom.: 0 Cov.: 32 AF XY: 0.0000527 AC XY: 38 AN XY: 721490

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44460

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25998

East Asian (EAS) AF: 0.000608 AC: 24 AN: 39496

South Asian (SAS) AF: 0.000302 AC: 26 AN: 86044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106294

Other (OTH) AF: 0.000267 AC: 16 AN: 59986

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152362 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74512

African (AFR) AF: 0.0000721 AC: 3 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000430 Hom.: 0

Bravo AF: 0.0000529

Asia WGS AF: 0.00318 AC: 11 AN: 3478

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

Feb 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4939+10C>T in Intron 33 of MYH14: This variant is not expected to have clinica l significance because it is not located within the conserved region of the spli ce consensus sequence and is not predicted to alter splicing. This variant has been identified in 7/ 8362 of East Asian chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs561531825). -

not provided Benign:1

Jan 06, 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	-0.49
CADD	Benign	17
DANN	Benign	0.80
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

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: rs561531825; hg19: chr19-50785109;