chr11-77147791-C-T

Variant names:

• chr11-77147791-C-T
• rs111033221
• NM_000260.4:c.133-7C>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.133-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00649 in 1,609,244 control chromosomes in the GnomAD database, including 48 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 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (45 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006355
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -0.724
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-77147791-C-T is Benign according to our data. Variant chr11-77147791-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43141.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00442 (673/152336) while in subpopulation NFE AF = 0.00723 (492/68022). AF 95% confidence interval is 0.0067. There are 3 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.133-7C>T		splice_region intron	N/A	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.133-7C>T		splice_region intron	N/A	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.100-7C>T		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.133-7C>T		splice_region intron	N/A	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.133-7C>T		splice_region intron	N/A	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.100-7C>T		splice_region intron	N/A	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 673 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00484 AC: 1161 AN: 239646 AF XY: 0.00486

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.00509

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00579

GnomAD4 exome AF: 0.00671 AC: 9773 AN: 1456908 Hom.: 45 Cov.: 34 AF XY: 0.00651 AC XY: 4717 AN XY: 724122

African (AFR) AF: 0.000958 AC: 32 AN: 33388

American (AMR) AF: 0.00341 AC: 151 AN: 44294

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 128 AN: 25900

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39596

South Asian (SAS) AF: 0.00118 AC: 100 AN: 84836

European-Finnish (FIN) AF: 0.00539 AC: 282 AN: 52300

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.00787 AC: 8744 AN: 1110590

Other (OTH) AF: 0.00548 AC: 330 AN: 60244

GnomAD4 genome AF: 0.00442 AC: 673 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00405 AC XY: 302 AN XY: 74488

African (AFR) AF: 0.00171 AC: 71 AN: 41580

American (AMR) AF: 0.00281 AC: 43 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00329 AC: 35 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68022

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00493 Hom.: 1

Bravo AF: 0.00449

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Autosomal dominant nonsyndromic hearing loss 11 (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (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	6.3
DANN	Benign	0.94
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0020
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: rs111033221; hg19: chr11-76858837;