rs680446

Variant names:

• chr19-50286683-G-A
• rs680446
• NM_001145809.2:c.4741G>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.4741G>A​(p.Val1581Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,573,118 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (32 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.79
• Publications: 7 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=0.010642201).
• BP6: Variant 19-50286683-G-A is Benign according to our data. Variant chr19-50286683-G-A is described in ClinVar as Benign. ClinVar VariationId is 44070.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 = 0.0101 (1544/152360) while in subpopulation AFR AF = 0.0344 (1432/41578). AF 95% confidence interval is 0.033. There are 32 homozygotes in GnomAd4. There are 736 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1544 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.4741G>A	p.Val1581Ile	missense	Exon 34 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.4642G>A	p.Val1548Ile	missense	Exon 33 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.4618G>A	p.Val1540Ile	missense	Exon 32 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.4741G>A	p.Val1581Ile	missense	Exon 34 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.4642G>A	p.Val1548Ile	missense	Exon 33 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.4642G>A	p.Val1548Ile	missense	Exon 33 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1544 AN: 152242 Hom.: 32 Cov.: 33

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00256 AC: 462 AN: 180632 AF XY: 0.00207

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00124 AC: 1767 AN: 1420758 Hom.: 22 Cov.: 31 AF XY: 0.00112 AC XY: 787 AN XY: 702914

African (AFR) AF: 0.0369 AC: 1208 AN: 32700

American (AMR) AF: 0.00246 AC: 93 AN: 37746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.00 AC: 0 AN: 37588

South Asian (SAS) AF: 0.000136 AC: 11 AN: 80908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50560

Middle Eastern (MID) AF: 0.00139 AC: 6 AN: 4310

European-Non Finnish (NFE) AF: 0.000301 AC: 329 AN: 1092636

Other (OTH) AF: 0.00204 AC: 120 AN: 58854

GnomAD4 genome AF: 0.0101 AC: 1544 AN: 152360 Hom.: 32 Cov.: 33 AF XY: 0.00988 AC XY: 736 AN XY: 74504

African (AFR) AF: 0.0344 AC: 1432 AN: 41578

American (AMR) AF: 0.00509 AC: 78 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68038

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00393 Hom.: 16

Bravo AF: 0.0109

ESP6500AA AF: 0.0278 AC: 116

ESP6500EA AF: 0.000595 AC: 5

ExAC AF: 0.00233 AC: 276

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.39
Sift	Benign	0.036	D
Sift4G	Benign	0.20	T
Polyphen		0.97	D
Vest4		0.31
MVP		0.71
MPC		0.32
ClinPred		0.032	T
GERP RS		4.5
Varity_R		0.054
gMVP		0.21
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: rs680446; hg19: chr19-50789940;