NM_001145809.2:c.4417G>A

Variant names:

• chr19-50281720-G-A
• rs112716976
• NM_001145809.2:c.4417G>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.4417G>A​(p.Val1473Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000357 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.00
• Publications: 6 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 (MetaRNN=0.014956325).
• BP6: Variant 19-50281720-G-A is Benign according to our data. Variant chr19-50281720-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227579.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 = 0.000965 (147/152372) while in subpopulation AFR AF = 0.00252 (105/41588). AF 95% confidence interval is 0.00213. There are 0 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 147 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	NM_001145809.2	MANE Select	c.4417G>A	p.Val1473Met	missense	Exon 33 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.4318G>A	p.Val1440Met	missense	Exon 32 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.4294G>A	p.Val1432Met	missense	Exon 31 of 41	NP_079005.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.4417G>A	p.Val1473Met	missense	Exon 33 of 43	ENSP00000493594.1
	MYH14	ENST00000425460.6	TSL:5	c.4318G>A	p.Val1440Met	missense	Exon 32 of 42	ENSP00000407879.1
	MYH14	ENST00000598205.5	TSL:5	c.4318G>A	p.Val1440Met	missense	Exon 32 of 42	ENSP00000472543.1

Frequencies

GnomAD3 genomes AF: 0.000965 AC: 147 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000434 AC: 105 AN: 241862 AF XY: 0.000407

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000609

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1460156 Hom.: 0 Cov.: 32 AF XY: 0.000324 AC XY: 235 AN XY: 726400

African (AFR) AF: 0.00257 AC: 86 AN: 33470

American (AMR) AF: 0.000179 AC: 8 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86224

European-Finnish (FIN) AF: 0.000498 AC: 26 AN: 52258

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.000244 AC: 271 AN: 1111674

Other (OTH) AF: 0.000448 AC: 27 AN: 60332

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74516

African (AFR) AF: 0.00252 AC: 105 AN: 41588

American (AMR) AF: 0.000457 AC: 7 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.000997

ESP6500AA AF: 0.000763 AC: 3

ESP6500EA AF: 0.000246 AC: 2

ExAC AF: 0.000400 AC: 48

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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)
-	-	1	MYH14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.060	N
REVEL	Benign	0.20
Sift	Benign	0.20	T
Sift4G	Benign	0.21	T
Polyphen		1.0	D
Vest4		0.28
MVP		0.62
MPC		0.35
ClinPred		0.025	T
GERP RS		2.7
Varity_R		0.041
gMVP		0.12
Mutation Taster		=93/7	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: rs112716976; hg19: chr19-50784977; COSMIC: COSV51824503; COSMIC: COSV51824503;