rs3745504

Variant names:

• chr19-50268352-G-A
• rs3745504
• NM_001145809.2:c.3018G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001145809.2(MYH14):​c.3018G>A​(p.Leu1006Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.55 in 1,572,796 control chromosomes in the GnomAD database, including 240,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (21810 hom., cov: 32)
  • Exomes 𝑓: 0.55 (218901 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 7.03
• Publications: 26 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-50268352-G-A is Benign according to our data. Variant chr19-50268352-G-A is described in ClinVar as Benign. ClinVar VariationId is 44062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

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.3018G>A	p.Leu1006Leu	synonymous	Exon 24 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.2919G>A	p.Leu973Leu	synonymous	Exon 23 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.2895G>A	p.Leu965Leu	synonymous	Exon 22 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.3018G>A	p.Leu1006Leu	synonymous	Exon 24 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.2919G>A	p.Leu973Leu	synonymous	Exon 23 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.2919G>A	p.Leu973Leu	synonymous	Exon 23 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80536 AN: 151878 Hom.: 21795 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.596

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.559 AC: 103065 AN: 184514 AF XY: 0.550

Gnomad AFR exome AF: 0.455

Gnomad AMR exome AF: 0.743

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.401

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.573

GnomAD4 exome AF: 0.552 AC: 783953 AN: 1420800 Hom.: 218901 Cov.: 58 AF XY: 0.548 AC XY: 385438 AN XY: 702904

African (AFR) AF: 0.440 AC: 14293 AN: 32466

American (AMR) AF: 0.727 AC: 28317 AN: 38932

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 11631 AN: 25342

East Asian (EAS) AF: 0.389 AC: 14488 AN: 37222

South Asian (SAS) AF: 0.450 AC: 36185 AN: 80474

European-Finnish (FIN) AF: 0.589 AC: 29316 AN: 49754

Middle Eastern (MID) AF: 0.488 AC: 2665 AN: 5460

European-Non Finnish (NFE) AF: 0.563 AC: 615316 AN: 1092172

Other (OTH) AF: 0.538 AC: 31742 AN: 58978

GnomAD4 genome AF: 0.530 AC: 80579 AN: 151996 Hom.: 21810 Cov.: 32 AF XY: 0.534 AC XY: 39695 AN XY: 74298

African (AFR) AF: 0.444 AC: 18418 AN: 41456

American (AMR) AF: 0.670 AC: 10231 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1582 AN: 3470

East Asian (EAS) AF: 0.391 AC: 2016 AN: 5150

South Asian (SAS) AF: 0.440 AC: 2116 AN: 4814

European-Finnish (FIN) AF: 0.596 AC: 6312 AN: 10596

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38115 AN: 67930

Other (OTH) AF: 0.536 AC: 1131 AN: 2110

Alfa AF: 0.547 Hom.: 74040

Bravo AF: 0.534

Asia WGS AF: 0.417 AC: 1447 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Autosomal dominant nonsyndromic hearing loss 4A (2)
-	-	2	not provided (2)
-	-	1	Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.4
DANN	Benign	0.94
PhyloP100		7.0
Mutation Taster		=52/48	polymorphism (auto)

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: rs3745504; hg19: chr19-50771609; COSMIC: COSV51811351;