rs34773557

Variant names:

• chr19-50217692-G-A
• rs34773557
• NM_001145809.2:c.483G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145809.2(MYH14):​c.483G>A​(p.Met161Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00899 in 1,614,010 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M161T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (94 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 5.79
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013709426).
• BP6: Variant 19-50217692-G-A is Benign according to our data. Variant chr19-50217692-G-A is described in ClinVar as Benign. ClinVar VariationId is 44073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0152 (2321/152332) while in subpopulation AFR AF = 0.0293 (1220/41576). AF 95% confidence interval is 0.028. There are 27 homozygotes in GnomAd4. There are 1130 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2321 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.483G>A	p.Met161Ile	missense	Exon 3 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.483G>A	p.Met161Ile	missense	Exon 3 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.483G>A	p.Met161Ile	missense	Exon 3 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.483G>A	p.Met161Ile	missense	Exon 3 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.483G>A	p.Met161Ile	missense	Exon 3 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.483G>A	p.Met161Ile	missense	Exon 3 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2315 AN: 152214 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0293

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00783

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00969 AC: 2415 AN: 249292 AF XY: 0.00916

Gnomad AFR exome AF: 0.0298

Gnomad AMR exome AF: 0.00976

Gnomad ASJ exome AF: 0.0262

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.00851

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.00834 AC: 12189 AN: 1461678 Hom.: 94 Cov.: 33 AF XY: 0.00800 AC XY: 5817 AN XY: 727122

African (AFR) AF: 0.0314 AC: 1051 AN: 33480

American (AMR) AF: 0.0101 AC: 450 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 648 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86258

European-Finnish (FIN) AF: 0.0117 AC: 626 AN: 53370

Middle Eastern (MID) AF: 0.0172 AC: 99 AN: 5768

European-Non Finnish (NFE) AF: 0.00770 AC: 8557 AN: 1111870

Other (OTH) AF: 0.0116 AC: 702 AN: 60374

GnomAD4 genome AF: 0.0152 AC: 2321 AN: 152332 Hom.: 27 Cov.: 32 AF XY: 0.0152 AC XY: 1130 AN XY: 74492

African (AFR) AF: 0.0293 AC: 1220 AN: 41576

American (AMR) AF: 0.0181 AC: 277 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4832

European-Finnish (FIN) AF: 0.0143 AC: 152 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00783 AC: 533 AN: 68034

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0106 Hom.: 34

Bravo AF: 0.0166

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.0274 AC: 119

ESP6500EA AF: 0.00772 AC: 66

ExAC AF: 0.00968 AC: 1174

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00905

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	4	not specified (4)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.016	D
Sift4G	Benign	0.11	T
Polyphen		0.71	P
Vest4		0.52
MutPred		0.49		Loss of ubiquitination at K165 (P = 0.074)
MVP		0.76
MPC		1.2
ClinPred		0.014	T
GERP RS		4.6
Varity_R		0.28
gMVP		0.58
Mutation Taster		=99/1	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: rs34773557; hg19: chr19-50720949;