11-77190144-G-C

Variant names:

• chr11-77190144-G-C
• rs111033391
• NM_000260.4:c.3750+5G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000260.4(MYO7A):​c.3750+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,368 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.367
• 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

ENSG00000296534 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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.3750+5G>C		splice_region intron	N/A	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.3750+5G>C		splice_region intron	N/A	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.3717+5G>C		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.3750+5G>C		splice_region intron	N/A	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.3750+5G>C		splice_region intron	N/A	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.3717+5G>C		splice_region intron	N/A	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403368 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 692898

African (AFR) AF: 0.00 AC: 0 AN: 31868

American (AMR) AF: 0.00 AC: 0 AN: 35846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25062

East Asian (EAS) AF: 0.00 AC: 0 AN: 36426

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78994

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5596

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082600

Other (OTH) AF: 0.00 AC: 0 AN: 58156

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.9
DANN	Benign	0.73
PhyloP100		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 3
DS_DL_spliceai		0.45		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs111033391; hg19: chr11-76901189;