NM_000260.4:c.6559-11C>T

Variant names:

• chr11-77214596-C-T
• rs34517202
• NM_000260.4:c.6559-11C>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.6559-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,556,648 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 32)
  • Exomes 𝑓: 0.022 (403 hom.)
• Consequence: MYO7A NM_000260.4 intron
• Scores: Splicing: ADA: 0.0002975
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0470
• Publications: 4 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=-0.54).
• BP6: Variant 11-77214596-C-T is Benign according to our data. Variant chr11-77214596-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0152 (2320/152312) while in subpopulation SAS AF = 0.0251 (121/4822). AF 95% confidence interval is 0.0216. There are 19 homozygotes in GnomAd4. There are 1125 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	NM_000260.4	MANE Select	c.6559-11C>T		intron	N/A	NP_000251.3
	MYO7A	NM_001127180.2		c.6439-11C>T		intron	N/A	NP_001120652.1
	MYO7A	NM_001369365.1		c.6412-11C>T		intron	N/A	NP_001356294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.6559-11C>T		intron	N/A	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.6439-11C>T		intron	N/A	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.6412-11C>T		intron	N/A	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2324 AN: 152194 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0236

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0225

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.0181 AC: 3287 AN: 181230 AF XY: 0.0192

Gnomad AFR exome AF: 0.00359

Gnomad AMR exome AF: 0.00820

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.000155

Gnomad FIN exome AF: 0.0206

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0221 AC: 31054 AN: 1404336 Hom.: 403 Cov.: 29 AF XY: 0.0222 AC XY: 15421 AN XY: 694742

African (AFR) AF: 0.00300 AC: 96 AN: 31982

American (AMR) AF: 0.00885 AC: 331 AN: 37392

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 370 AN: 25304

East Asian (EAS) AF: 0.0000810 AC: 3 AN: 37022

South Asian (SAS) AF: 0.0256 AC: 2042 AN: 79822

European-Finnish (FIN) AF: 0.0236 AC: 1187 AN: 50318

Middle Eastern (MID) AF: 0.0278 AC: 159 AN: 5712

European-Non Finnish (NFE) AF: 0.0237 AC: 25591 AN: 1078260

Other (OTH) AF: 0.0218 AC: 1275 AN: 58524

GnomAD4 genome AF: 0.0152 AC: 2320 AN: 152312 Hom.: 19 Cov.: 32 AF XY: 0.0151 AC XY: 1125 AN XY: 74470

African (AFR) AF: 0.00435 AC: 181 AN: 41566

American (AMR) AF: 0.00934 AC: 143 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0251 AC: 121 AN: 4822

European-Finnish (FIN) AF: 0.0236 AC: 251 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0225 AC: 1531 AN: 68024

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0104 Hom.: 2

Bravo AF: 0.0136

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	-	1	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.4
DANN	Benign	0.84
PhyloP100		0.047
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.24
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: rs34517202; hg19: chr11-76925641;