rs35453633

Variant names:

• chr19-50286538-C-T
• rs35453633
• NM_001145809.2:c.4596C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145809.2(MYH14):​c.4596C>T​(p.Ala1532Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,613,374 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (40 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.75
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039724708).
• BP6: Variant 19-50286538-C-T is Benign according to our data. Variant chr19-50286538-C-T is described in ClinVar as Benign. ClinVar VariationId is 178618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1741/152300) while in subpopulation AFR AF = 0.0396 (1645/41554). AF 95% confidence interval is 0.038. There are 40 homozygotes in GnomAd4. There are 831 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1741 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.4596C>T	p.Ala1532Ala	synonymous	Exon 34 of 43	NP_001139281.1
	MYH14	NM_001077186.2		c.4497C>T	p.Ala1499Ala	synonymous	Exon 33 of 42	NP_001070654.1
	MYH14	NM_024729.4		c.4473C>T	p.Ala1491Ala	synonymous	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.4596C>T	p.Ala1532Ala	synonymous	Exon 34 of 43	ENSP00000493594.1
	MYH14	ENST00000425460.6	TSL:5	c.4497C>T	p.Ala1499Ala	synonymous	Exon 33 of 42	ENSP00000407879.1
	MYH14	ENST00000598205.5	TSL:5	c.4497C>T	p.Ala1499Ala	synonymous	Exon 33 of 42	ENSP00000472543.1

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1743 AN: 152182 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00301 AC: 740 AN: 245672 AF XY: 0.00245

Gnomad AFR exome AF: 0.0414

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00117 AC: 1710 AN: 1461074 Hom.: 28 Cov.: 31 AF XY: 0.00101 AC XY: 731 AN XY: 726742

African (AFR) AF: 0.0392 AC: 1313 AN: 33472

American (AMR) AF: 0.00275 AC: 123 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39682

South Asian (SAS) AF: 0.000535 AC: 46 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000738 AC: 82 AN: 1111684

Other (OTH) AF: 0.00220 AC: 133 AN: 60354

GnomAD4 genome AF: 0.0114 AC: 1741 AN: 152300 Hom.: 40 Cov.: 33 AF XY: 0.0112 AC XY: 831 AN XY: 74480

African (AFR) AF: 0.0396 AC: 1645 AN: 41554

American (AMR) AF: 0.00412 AC: 63 AN: 15300

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

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

Other (OTH) AF: 0.0109 AC: 23 AN: 2116

Alfa AF: 0.00660 Hom.: 10

Bravo AF: 0.0130

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0382 AC: 158

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00368 AC: 445

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.7
DANN	Benign	0.72
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0040	T
PhyloP100		-3.8
Sift4G	Benign	0.60	T
Vest4		0.091
MVP		0.24
GERP RS		-9.1
Mutation Taster		=99/1	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: rs35453633; hg19: chr19-50789795;