chr11-77179045-G-A

Variant names:

• chr11-77179045-G-A
• rs111033229
• NM_000260.4:c.2283G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000260.4(MYO7A):​c.2283G>A​(p.Arg761Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,602,990 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO7A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.006271
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 2.35
• Publications: 3 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 Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 1

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

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-77179045-G-A is Benign according to our data. Variant chr11-77179045-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43179.
• BP7: Synonymous conserved (PhyloP=2.35 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.2283G>A	p.Arg761Arg	splice_region synonymous	Exon 20 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.2283G>A	p.Arg761Arg	splice_region synonymous	Exon 20 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.2250G>A	p.Arg750Arg	splice_region synonymous	Exon 21 of 50	NP_001356294.1	Q13402-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.2283G>A	p.Arg761Arg	splice_region synonymous	Exon 20 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.2283G>A	p.Arg761Arg	splice_region synonymous	Exon 20 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.2250G>A	p.Arg750Arg	splice_region synonymous	Exon 21 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000494 AC: 115 AN: 232976 AF XY: 0.000530

Gnomad AFR exome AF: 0.000365

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000467

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000965

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000868 AC: 1259 AN: 1450764 Hom.: 1 Cov.: 30 AF XY: 0.000872 AC XY: 628 AN XY: 720498

African (AFR) AF: 0.000180 AC: 6 AN: 33290

American (AMR) AF: 0.0000458 AC: 2 AN: 43656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.000127 AC: 5 AN: 39300

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51420

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5754

European-Non Finnish (NFE) AF: 0.00108 AC: 1199 AN: 1107424

Other (OTH) AF: 0.000733 AC: 44 AN: 60010

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74372

African (AFR) AF: 0.000265 AC: 11 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000804 Hom.: 0

Bravo AF: 0.000521

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	Hearing impairment (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	MYO7A-related disorder (1)
-	-	1	not specified (1)
-	1	-	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.47
PhyloP100		2.4
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.040		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: rs111033229; hg19: chr11-76890091;