rs537153044

Variant names:

• chr19-50244332-A-G
• rs537153044
• NM_001145809.2:c.1205A>G

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.1205A>G​(p.Asn402Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000914 in 1,613,354 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00096 (21 hom.)
• Consequence: MYH14 NM_001145809.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 9.21
• 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), PanelApp Australia
• peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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=0.00941354).
• BP6: Variant 19-50244332-A-G is Benign according to our data. Variant chr19-50244332-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 164171.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 = 0.00048 (73/152052) while in subpopulation SAS AF = 0.0147 (71/4816). AF 95% confidence interval is 0.012. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 73 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.1205A>G	p.Asn402Ser	missense	Exon 11 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.1205A>G	p.Asn402Ser	missense	Exon 11 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.1181A>G	p.Asn394Ser	missense	Exon 10 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.1205A>G	p.Asn402Ser	missense	Exon 11 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.1205A>G	p.Asn402Ser	missense	Exon 11 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.1205A>G	p.Asn402Ser	missense	Exon 11 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 151934 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00212 AC: 522 AN: 246456 AF XY: 0.00293

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000959 AC: 1402 AN: 1461302 Hom.: 21 Cov.: 32 AF XY: 0.00142 AC XY: 1030 AN XY: 726918

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.0154 AC: 1331 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53056

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111822

Other (OTH) AF: 0.00109 AC: 66 AN: 60370

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152052 Hom.: 0 Cov.: 31 AF XY: 0.000700 AC XY: 52 AN XY: 74316

African (AFR) AF: 0.0000241 AC: 1 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000910 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.00243 AC: 294

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.051
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	-0.0046	T
MutationAssessor	Benign	0.97	L
PhyloP100		9.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.016	D
Sift4G	Benign	0.099	T
Polyphen		0.27	B
Vest4		0.58
MVP		0.77
MPC		1.0
ClinPred		0.090	T
GERP RS		3.4
Varity_R		0.27
gMVP		0.17
Mutation Taster		=90/10	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: rs537153044; hg19: chr19-50747589;