rs200351672

Variant names:

• chr19-50266974-G-A
• rs200351672
• NM_001145809.2:c.2792G>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.2792G>A​(p.Arg931His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,568,210 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. R931G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.06
• 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=0.0049929917).
• BP6: Variant 19-50266974-G-A is Benign according to our data. Variant chr19-50266974-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44059.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 = 0.00438 (667/152172) while in subpopulation AFR AF = 0.0119 (492/41500). AF 95% confidence interval is 0.011. There are 6 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 667 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.2792G>A	p.Arg931His	missense	Exon 23 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.2693G>A	p.Arg898His	missense	Exon 22 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.2669G>A	p.Arg890His	missense	Exon 21 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2792G>A	p.Arg931His	missense	Exon 23 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.2693G>A	p.Arg898His	missense	Exon 22 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.2693G>A	p.Arg898His	missense	Exon 22 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.00439 AC: 667 AN: 152054 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00205 AC: 363 AN: 177306 AF XY: 0.00173

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.00441

Gnomad ASJ exome AF: 0.000459

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000887

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00108 AC: 1523 AN: 1416038 Hom.: 5 Cov.: 33 AF XY: 0.00100 AC XY: 701 AN XY: 699796

African (AFR) AF: 0.0147 AC: 480 AN: 32732

American (AMR) AF: 0.00438 AC: 165 AN: 37640

Ashkenazi Jewish (ASJ) AF: 0.000395 AC: 10 AN: 25326

East Asian (EAS) AF: 0.00 AC: 0 AN: 37576

South Asian (SAS) AF: 0.000609 AC: 49 AN: 80510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49488

Middle Eastern (MID) AF: 0.00618 AC: 32 AN: 5182

European-Non Finnish (NFE) AF: 0.000602 AC: 656 AN: 1088916

Other (OTH) AF: 0.00223 AC: 131 AN: 58668

GnomAD4 genome AF: 0.00438 AC: 667 AN: 152172 Hom.: 6 Cov.: 32 AF XY: 0.00421 AC XY: 313 AN XY: 74396

African (AFR) AF: 0.0119 AC: 492 AN: 41500

American (AMR) AF: 0.00503 AC: 77 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68002

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00220 Hom.: 1

Bravo AF: 0.00539

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0120 AC: 49

ESP6500EA AF: 0.00121 AC: 10

ExAC AF: 0.00144 AC: 167

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.088
Sift	Benign	0.38	T
Sift4G	Benign	0.20	T
Polyphen		0.018	B
Vest4		0.20
MVP		0.79
MPC		1.2
ClinPred		0.024	T
GERP RS		0.87
Varity_R		0.041
gMVP		0.13
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: rs200351672; hg19: chr19-50770231;