rs372623270

Variant names:

• chr11-77190804-G-A
• rs372623270
• NM_000260.4:c.3858G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77190804-G-A
• chr11-77190804-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.3858G>A​(p.Ala1286Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,591,584 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -3.47
• Publications: 0 publications found

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

MYO7A Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
• Usher syndrome type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant nonsyndromic hearing loss 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-77190804-G-A is Benign according to our data. Variant chr11-77190804-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 306184.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000229 (330/1439652) while in subpopulation EAS AF = 0.00452 (174/38520). AF 95% confidence interval is 0.00397. There are 3 homozygotes in GnomAdExome4. There are 163 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000260.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.3858G>A	p.Ala1286Ala	synonymous	Exon 30 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.3858G>A	p.Ala1286Ala	synonymous	Exon 30 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.3825G>A	p.Ala1275Ala	synonymous	Exon 31 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.3858G>A	p.Ala1286Ala	synonymous	Exon 30 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.3858G>A	p.Ala1286Ala	synonymous	Exon 30 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.3825G>A	p.Ala1275Ala	synonymous	Exon 31 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151814 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000164 AC: 35 AN: 213034 AF XY: 0.000183

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000326

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.000229 AC: 330 AN: 1439652 Hom.: 3 Cov.: 31 AF XY: 0.000228 AC XY: 163 AN XY: 713920

African (AFR) AF: 0.0000304 AC: 1 AN: 32938

American (AMR) AF: 0.0000481 AC: 2 AN: 41538

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 61 AN: 25678

East Asian (EAS) AF: 0.00452 AC: 174 AN: 38520

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000708 AC: 78 AN: 1101626

Other (OTH) AF: 0.000184 AC: 11 AN: 59658

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151932 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74232

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000776 AC: 4 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10540

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	MYO7A-related disorder (1)
-	-	1	not specified (1)
-	1	-	Usher syndrome type 1 (1)
-	1	-	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.5
DANN	Benign	0.78
PhyloP100		-3.5
Mutation Taster		=65/35	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: rs372623270; hg19: chr11-76901849; COSMIC: COSV68684606;