rs1316683575

Variant names:

• chr19-50210397-G-A
• rs1316683575
• NM_001145809.2:c.32G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001145809.2(MYH14):​c.32G>A​(p.Arg11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000569 in 1,580,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.26
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1961394).
• BS2: High AC in GnomAdExome4 at 8 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.32G>A	p.Arg11Gln	missense	Exon 2 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.32G>A	p.Arg11Gln	missense	Exon 2 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.32G>A	p.Arg11Gln	missense	Exon 2 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.32G>A	p.Arg11Gln	missense	Exon 2 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.32G>A	p.Arg11Gln	missense	Exon 2 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.32G>A	p.Arg11Gln	missense	Exon 2 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000157 AC: 3 AN: 191174 AF XY: 0.00000944

Gnomad AFR exome AF: 0.000239

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000206

GnomAD4 exome AF: 0.00000560 AC: 8 AN: 1428806 Hom.: 0 Cov.: 31 AF XY: 0.00000423 AC XY: 3 AN XY: 709086

African (AFR) AF: 0.0000648 AC: 2 AN: 30870

American (AMR) AF: 0.00 AC: 0 AN: 41510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37176

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1097504

Other (OTH) AF: 0.00 AC: 0 AN: 58846

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	MYH14-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0081	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.000088
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.33	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.49	P
Vest4		0.25
MutPred		0.29		Loss of MoRF binding (P = 0.0167)
MVP		0.50
MPC		0.54
ClinPred		0.20	T
GERP RS		4.3
PromoterAI		-0.12	Neutral
Varity_R		0.13
gMVP		0.48
Mutation Taster		=98/2	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: rs1316683575; hg19: chr19-50713654; COSMIC: COSV51826644;