chr19-50282129-A-G

Variant names:

• chr19-50282129-A-G
• rs667907
• NM_001145809.2:c.4539+287A>G

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.4539+287A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 152,026 control chromosomes in the GnomAD database, including 11,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.36 (11113 hom., cov: 33)
• Consequence: MYH14 NM_001145809.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.633
• 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=-1.02).
• BP6: Variant 19-50282129-A-G is Benign according to our data. Variant chr19-50282129-A-G is described in ClinVar as [Benign]. Clinvar id is 1272242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH14	NM_001145809.2	c.4539+287A>G		intron_variant	Intron 33 of 42	ENST00000642316.2	NP_001139281.1
MYH14	NM_001077186.2	c.4440+287A>G		intron_variant	Intron 32 of 41		NP_001070654.1
MYH14	NM_024729.4	c.4416+287A>G		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+287A>G		intron_variant	Intron 33 of 42		NM_001145809.2	ENSP00000493594.1

Frequencies

GnomAD3 genomes AF: 0.364 AC: 55311 AN: 151908 Hom.: 11100 Cov.: 33

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.360

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.364 AC: 55354 AN: 152026 Hom.: 11113 Cov.: 33 AF XY: 0.359 AC XY: 26690 AN XY: 74296

African (AFR) AF: 0.535 AC: 22187 AN: 41464

American (AMR) AF: 0.286 AC: 4367 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1012 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1255 AN: 5164

South Asian (SAS) AF: 0.291 AC: 1402 AN: 4822

European-Finnish (FIN) AF: 0.296 AC: 3126 AN: 10544

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20687 AN: 67970

Other (OTH) AF: 0.356 AC: 752 AN: 2112

Alfa AF: 0.323 Hom.: 38348

Bravo AF: 0.372

Asia WGS AF: 0.260 AC: 907 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

- -

Nov 12, 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	-1.0
CADD	Benign	0.50
DANN	Benign	0.30
PhyloP100		-0.63
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: rs667907; hg19: chr19-50785386; COSMIC: COSV107267481; COSMIC: COSV107267481;