rs138987081

Variant names:

• chr19-50268175-C-T
• rs138987081
• NM_001145809.2:c.2841C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145809.2(MYH14):​c.2841C>T​(p.Arg947Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,547,272 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 33)
  • Exomes 𝑓: 0.014 (169 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.72
• Publications: 3 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 19-50268175-C-T is Benign according to our data. Variant chr19-50268175-C-T is described in ClinVar as Benign. ClinVar VariationId is 44061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0102 (1558/152340) while in subpopulation NFE AF = 0.0152 (1034/68038). AF 95% confidence interval is 0.0144. There are 14 homozygotes in GnomAd4. There are 748 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1558 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.2841C>T	p.Arg947Arg	synonymous	Exon 24 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.2742C>T	p.Arg914Arg	synonymous	Exon 23 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.2718C>T	p.Arg906Arg	synonymous	Exon 22 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2841C>T	p.Arg947Arg	synonymous	Exon 24 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.2742C>T	p.Arg914Arg	synonymous	Exon 23 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.2742C>T	p.Arg914Arg	synonymous	Exon 23 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1558 AN: 152222 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0100 AC: 1529 AN: 152730 AF XY: 0.0102

Gnomad AFR exome AF: 0.00274

Gnomad AMR exome AF: 0.00847

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.0140 AC: 19586 AN: 1394932 Hom.: 169 Cov.: 34 AF XY: 0.0139 AC XY: 9541 AN XY: 688116

African (AFR) AF: 0.00165 AC: 52 AN: 31594

American (AMR) AF: 0.00888 AC: 318 AN: 35794

Ashkenazi Jewish (ASJ) AF: 0.00262 AC: 66 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35788

South Asian (SAS) AF: 0.00449 AC: 356 AN: 79206

European-Finnish (FIN) AF: 0.0225 AC: 1030 AN: 45798

Middle Eastern (MID) AF: 0.00638 AC: 29 AN: 4548

European-Non Finnish (NFE) AF: 0.0157 AC: 16960 AN: 1079114

Other (OTH) AF: 0.0134 AC: 775 AN: 57906

GnomAD4 genome AF: 0.0102 AC: 1558 AN: 152340 Hom.: 14 Cov.: 33 AF XY: 0.0100 AC XY: 748 AN XY: 74490

African (AFR) AF: 0.00269 AC: 112 AN: 41580

American (AMR) AF: 0.00863 AC: 132 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.0203 AC: 216 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1034 AN: 68038

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0124 Hom.: 5

Bravo AF: 0.00942

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.4
DANN	Benign	0.85
PhyloP100		-1.7
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: rs138987081; hg19: chr19-50771432;