rs540145750

Variant names:

• chr11-77177648-G-A
• rs540145750
• NM_000260.4:c.2282+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-77177648-G-A
• chr11-77177648-G-C
• chr11-77177648-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000260.4(MYO7A):​c.2282+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,603,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.9914
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.52
• 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 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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.2282+5G>A		splice_region intron	N/A	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.2282+5G>A		splice_region intron	N/A	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.2249+5G>A		splice_region intron	N/A	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.2282+5G>A		splice_region intron	N/A	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.2282+5G>A		splice_region intron	N/A	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.2249+5G>A		splice_region intron	N/A	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152100 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000350 AC: 81 AN: 231636 AF XY: 0.000350

Gnomad AFR exome AF: 0.0000739

Gnomad AMR exome AF: 0.000455

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00204

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000201 AC: 292 AN: 1451434 Hom.: 0 Cov.: 30 AF XY: 0.000205 AC XY: 148 AN XY: 721034

African (AFR) AF: 0.0000601 AC: 2 AN: 33302

American (AMR) AF: 0.000366 AC: 16 AN: 43694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.0000595 AC: 5 AN: 84004

European-Finnish (FIN) AF: 0.00161 AC: 84 AN: 52224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000150 AC: 166 AN: 1107140

Other (OTH) AF: 0.000316 AC: 19 AN: 60044

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74424

African (AFR) AF: 0.000193 AC: 8 AN: 41520

American (AMR) AF: 0.000915 AC: 14 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67994

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.000295

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (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	-0.71
CADD	Benign	19
DANN	Benign	0.82
PhyloP100		2.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.10		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: rs540145750; hg19: chr11-76888694;