rs4802666

Variant names:

• chr19-50217817-G-A
• rs4802666
• NM_001145809.2:c.562+46G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001145809.2(MYH14):​c.562+46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,597,016 control chromosomes in the GnomAD database, including 78,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5147 hom., cov: 31)
  • Exomes 𝑓: 0.31 (72855 hom.)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.420
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-50217817-G-A is Benign according to our data. Variant chr19-50217817-G-A is described in ClinVar as Benign. ClinVar VariationId is 1295265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.562+46G>A		intron_variant	Intron 3 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.562+46G>A		intron_variant	Intron 3 of 41		NP_001070654.1
MYH14	NM_024729.4	c.562+46G>A		intron_variant	Intron 3 of 40		NP_079005.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH14	ENST00000642316.2	c.562+46G>A		intron_variant	Intron 3 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37443 AN: 151944 Hom.: 5142 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.270

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.282 AC: 66054 AN: 234006 AF XY: 0.294

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.313 AC: 451823 AN: 1444954 Hom.: 72855 Cov.: 33 AF XY: 0.316 AC XY: 226460 AN XY: 717672

African (AFR) AF: 0.112 AC: 3736 AN: 33268

American (AMR) AF: 0.196 AC: 8691 AN: 44376

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7223 AN: 25552

East Asian (EAS) AF: 0.273 AC: 10783 AN: 39536

South Asian (SAS) AF: 0.383 AC: 32732 AN: 85472

European-Finnish (FIN) AF: 0.272 AC: 12838 AN: 47178

Middle Eastern (MID) AF: 0.322 AC: 1618 AN: 5026

European-Non Finnish (NFE) AF: 0.322 AC: 356097 AN: 1104798

Other (OTH) AF: 0.303 AC: 18105 AN: 59748

GnomAD4 genome AF: 0.246 AC: 37449 AN: 152062 Hom.: 5147 Cov.: 31 AF XY: 0.245 AC XY: 18175 AN XY: 74320

African (AFR) AF: 0.118 AC: 4883 AN: 41500

American (AMR) AF: 0.216 AC: 3306 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1028 AN: 3466

East Asian (EAS) AF: 0.250 AC: 1287 AN: 5144

South Asian (SAS) AF: 0.383 AC: 1840 AN: 4810

European-Finnish (FIN) AF: 0.270 AC: 2855 AN: 10568

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21380 AN: 67964

Other (OTH) AF: 0.256 AC: 542 AN: 2116

Alfa AF: 0.292 Hom.: 26707

Bravo AF: 0.235

Asia WGS AF: 0.317 AC: 1100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: 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	-0.86
CADD	Benign	1.6
DANN	Benign	0.69
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

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: rs4802666; hg19: chr19-50721074;