rs4801822

Variant names:

• chr19-50223313-G-A
• rs4801822
• NM_001145809.2:c.657G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-50223313-G-A
• chr19-50223313-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001145809.2(MYH14):​c.657G>A​(p.Ala219Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,592,160 control chromosomes in the GnomAD database, including 309,869 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A219A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (21887 hom., cov: 33)
  • Exomes 𝑓: 0.63 (287982 hom.)
• Consequence: MYH14 NM_001145809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.92
• Publications: 30 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-50223313-G-A is Benign according to our data. Variant chr19-50223313-G-A is described in ClinVar as Benign. ClinVar VariationId is 44079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.632 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.657G>A	p.Ala219Ala	synonymous	Exon 5 of 43	NP_001139281.1	Q7Z406-2
	MYH14	NM_001077186.2		c.657G>A	p.Ala219Ala	synonymous	Exon 5 of 42	NP_001070654.1	Q7Z406-6
	MYH14	NM_024729.4		c.657G>A	p.Ala219Ala	synonymous	Exon 5 of 41	NP_079005.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYH14	ENST00000642316.2	MANE Select	c.657G>A	p.Ala219Ala	synonymous	Exon 5 of 43	ENSP00000493594.1	Q7Z406-2
	MYH14	ENST00000599920.5	TSL:1	c.657G>A	p.Ala219Ala	synonymous	Exon 5 of 24	ENSP00000469573.1	M0QY43
	MYH14	ENST00000425460.6	TSL:5	c.657G>A	p.Ala219Ala	synonymous	Exon 5 of 42	ENSP00000407879.1	Q7Z406-6

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76331 AN: 152026 Hom.: 21887 Cov.: 33

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.596

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.579

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.637

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.569 AC: 122450 AN: 215144 AF XY: 0.582

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.444

Gnomad ASJ exome AF: 0.527

Gnomad EAS exome AF: 0.570

Gnomad FIN exome AF: 0.652

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.580

GnomAD4 exome AF: 0.627 AC: 902177 AN: 1440016 Hom.: 287982 Cov.: 51 AF XY: 0.627 AC XY: 448254 AN XY: 714584

African (AFR) AF: 0.196 AC: 6476 AN: 32980

American (AMR) AF: 0.450 AC: 18169 AN: 40362

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 13552 AN: 25734

East Asian (EAS) AF: 0.637 AC: 24479 AN: 38438

South Asian (SAS) AF: 0.615 AC: 51582 AN: 83904

European-Finnish (FIN) AF: 0.650 AC: 33804 AN: 52044

Middle Eastern (MID) AF: 0.508 AC: 2921 AN: 5746

European-Non Finnish (NFE) AF: 0.650 AC: 715847 AN: 1101166

Other (OTH) AF: 0.593 AC: 35347 AN: 59642

GnomAD4 genome AF: 0.502 AC: 76338 AN: 152144 Hom.: 21887 Cov.: 33 AF XY: 0.505 AC XY: 37532 AN XY: 74380

African (AFR) AF: 0.208 AC: 8628 AN: 41520

American (AMR) AF: 0.506 AC: 7733 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1851 AN: 3472

East Asian (EAS) AF: 0.578 AC: 2981 AN: 5156

South Asian (SAS) AF: 0.629 AC: 3029 AN: 4816

European-Finnish (FIN) AF: 0.663 AC: 7026 AN: 10596

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.637 AC: 43329 AN: 67974

Other (OTH) AF: 0.511 AC: 1081 AN: 2114

Alfa AF: 0.585 Hom.: 38013

Bravo AF: 0.474

Asia WGS AF: 0.582 AC: 2022 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	-0.58
CADD	Benign	0.17
DANN	Benign	0.66
PhyloP100		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs4801822; hg19: chr19-50726570; COSMIC: COSV51809625;