rs547836952

Variant names:

• chr19-50263326-G-A
• rs547836952
• NM_001145809.2:c.2600G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50263326-G-A
• chr19-50263326-G-T

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.2600G>A​(p.Arg867His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000499 in 1,562,446 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R867C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.88
• Publications: 2 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=0.010991424).
• BP6: Variant 19-50263326-G-A is Benign according to our data. Variant chr19-50263326-G-A is described in ClinVar as Benign. ClinVar VariationId is 329922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000387 (59/152306) while in subpopulation SAS AF = 0.00996 (48/4818). AF 95% confidence interval is 0.00772. There are 1 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 59 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.2600G>A	p.Arg867His	missense	Exon 22 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.2501G>A	p.Arg834His	missense	Exon 21 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.2477G>A	p.Arg826His	missense	Exon 20 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.2600G>A	p.Arg867His	missense	Exon 22 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.2501G>A	p.Arg834His	missense	Exon 21 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.2501G>A	p.Arg834His	missense	Exon 21 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00106 AC: 192 AN: 180606 AF XY: 0.00140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000153

Gnomad ASJ exome AF: 0.000342

Gnomad EAS exome AF: 0.000155

Gnomad FIN exome AF: 0.000113

Gnomad NFE exome AF: 0.0000520

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.000511 AC: 721 AN: 1410140 Hom.: 7 Cov.: 30 AF XY: 0.000714 AC XY: 498 AN XY: 697200

African (AFR) AF: 0.0000313 AC: 1 AN: 31944

American (AMR) AF: 0.000134 AC: 5 AN: 37334

Ashkenazi Jewish (ASJ) AF: 0.000159 AC: 4 AN: 25096

East Asian (EAS) AF: 0.000109 AC: 4 AN: 36822

South Asian (SAS) AF: 0.00807 AC: 642 AN: 79514

European-Finnish (FIN) AF: 0.000140 AC: 7 AN: 50122

Middle Eastern (MID) AF: 0.000709 AC: 4 AN: 5642

European-Non Finnish (NFE) AF: 0.0000304 AC: 33 AN: 1085278

Other (OTH) AF: 0.000360 AC: 21 AN: 58388

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74468

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00996 AC: 48 AN: 4818

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

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

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

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.00106 AC: 127

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.61	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.043	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.82
MPC		1.5
ClinPred		0.086	T
GERP RS		3.0
Varity_R		0.069
gMVP		0.61
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs547836952; hg19: chr19-50766583;