NM_000260.4:c.286-5C>T

Variant names:

• chr11-77155902-C-T
• rs111033471
• NM_000260.4:c.286-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000260.4(MYO7A):​c.286-5C>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 0.00275 in 1,584,686 control chromosomes in the GnomAD database, including 91 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (43 hom.)
• Consequence: MYO7A NM_000260.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002144
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.266
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-77155902-C-T is Benign according to our data. Variant chr11-77155902-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1988/152322) while in subpopulation AFR AF = 0.0441 (1832/41552). AF 95% confidence interval is 0.0424. There are 48 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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.286-5C>T		splice_region intron	N/A	NP_000251.3
	MYO7A	NM_001127180.2		c.286-5C>T		splice_region intron	N/A	NP_001120652.1
	MYO7A	NM_001369365.1		c.253-5C>T		splice_region intron	N/A	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.286-5C>T		splice_region intron	N/A	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.286-5C>T		splice_region intron	N/A	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.253-5C>T		splice_region intron	N/A	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1982 AN: 152204 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0441

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00384 AC: 855 AN: 222588 AF XY: 0.00276

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.000364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000280

Gnomad OTH exome AF: 0.00126

GnomAD4 exome AF: 0.00166 AC: 2372 AN: 1432364 Hom.: 43 Cov.: 31 AF XY: 0.00141 AC XY: 1001 AN XY: 708092

African (AFR) AF: 0.0468 AC: 1539 AN: 32894

American (AMR) AF: 0.00187 AC: 79 AN: 42248

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 370 AN: 25224

East Asian (EAS) AF: 0.000207 AC: 8 AN: 38674

South Asian (SAS) AF: 0.0000853 AC: 7 AN: 82084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52162

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5694

European-Non Finnish (NFE) AF: 0.000108 AC: 118 AN: 1094172

Other (OTH) AF: 0.00417 AC: 247 AN: 59212

GnomAD4 genome AF: 0.0131 AC: 1988 AN: 152322 Hom.: 48 Cov.: 33 AF XY: 0.0124 AC XY: 921 AN XY: 74488

African (AFR) AF: 0.0441 AC: 1832 AN: 41552

American (AMR) AF: 0.00379 AC: 58 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3472

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68034

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00582 Hom.: 3

Bravo AF: 0.0145

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	-	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	-0.81
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		-0.27
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs111033471; hg19: chr11-76866948;