rs140118363

Variant names:

• chr19-50286627-G-A
• rs140118363
• NM_001145809.2:c.4685G>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.4685G>A​(p.Arg1562Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,596,622 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1562W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 7.85
• Publications: 4 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=0.011157781).
• BP6: Variant 19-50286627-G-A is Benign according to our data. Variant chr19-50286627-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178421.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 = 0.00147 (224/152318) while in subpopulation AFR AF = 0.005 (208/41566). AF 95% confidence interval is 0.00445. There are 0 homozygotes in GnomAd4. There are 106 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 224 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.4685G>A	p.Arg1562Gln	missense	Exon 34 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.4586G>A	p.Arg1529Gln	missense	Exon 33 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.4562G>A	p.Arg1521Gln	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.4685G>A	p.Arg1562Gln	missense	Exon 34 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000425460.6	TSL:5	c.4586G>A	p.Arg1529Gln	missense	Exon 33 of 42	ENSP00000407879.1	Q7Z406-6
	MYH14	ENST00000598205.5	TSL:5	c.4586G>A	p.Arg1529Gln	missense	Exon 33 of 42	ENSP00000472543.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000368 AC: 79 AN: 214688 AF XY: 0.000275

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0000995

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000631

Gnomad FIN exome AF: 0.0000545

Gnomad NFE exome AF: 0.0000312

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000136 AC: 196 AN: 1444304 Hom.: 1 Cov.: 31 AF XY: 0.000114 AC XY: 82 AN XY: 716710

African (AFR) AF: 0.00463 AC: 154 AN: 33266

American (AMR) AF: 0.000145 AC: 6 AN: 41280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39072

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83336

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1104040

Other (OTH) AF: 0.000251 AC: 15 AN: 59788

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74470

African (AFR) AF: 0.00500 AC: 208 AN: 41566

American (AMR) AF: 0.000849 AC: 13 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.00162

ESP6500AA AF: 0.00471 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000414 AC: 50

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.84
MPC		0.68
ClinPred		0.082	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.40
Mutation Taster		=58/42	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: rs140118363; hg19: chr19-50789884;