rs111033230

Variant names:

• chr11-77213940-C-T
• rs111033230
• NM_000260.4:c.6519C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000260.4(MYO7A):​c.6519C>T​(p.Asn2173Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 1,614,090 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 34)
  • Exomes 𝑓: 0.013 (154 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 2.52
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 11-77213940-C-T is Benign according to our data. Variant chr11-77213940-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43331.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0118 (1805/152384) while in subpopulation NFE AF = 0.014 (955/68036). AF 95% confidence interval is 0.0133. There are 12 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.6519C>T	p.Asn2173Asn	synonymous	Exon 48 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.6399C>T	p.Asn2133Asn	synonymous	Exon 48 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.6372C>T	p.Asn2124Asn	synonymous	Exon 49 of 50	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.6519C>T	p.Asn2173Asn	synonymous	Exon 48 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.6399C>T	p.Asn2133Asn	synonymous	Exon 48 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.6372C>T	p.Asn2124Asn	synonymous	Exon 49 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152266 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.0108

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0113 AC: 2812 AN: 249248 AF XY: 0.0116

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.00695

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00492

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0128 AC: 18744 AN: 1461706 Hom.: 154 Cov.: 38 AF XY: 0.0128 AC XY: 9310 AN XY: 727134

African (AFR) AF: 0.0119 AC: 397 AN: 33480

American (AMR) AF: 0.00729 AC: 326 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 813 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00995 AC: 858 AN: 86258

European-Finnish (FIN) AF: 0.00491 AC: 262 AN: 53396

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5768

European-Non Finnish (NFE) AF: 0.0136 AC: 15091 AN: 1111870

Other (OTH) AF: 0.0150 AC: 904 AN: 60374

GnomAD4 genome AF: 0.0118 AC: 1805 AN: 152384 Hom.: 12 Cov.: 34 AF XY: 0.0116 AC XY: 862 AN XY: 74518

African (AFR) AF: 0.0108 AC: 449 AN: 41608

American (AMR) AF: 0.00895 AC: 137 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

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

South Asian (SAS) AF: 0.0118 AC: 57 AN: 4830

European-Finnish (FIN) AF: 0.00583 AC: 62 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 955 AN: 68036

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0147 Hom.: 14

Bravo AF: 0.0121

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0139

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.4
DANN	Benign	0.73
PhyloP100		2.5
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs111033230; hg19: chr11-76924985; COSMIC: COSV108138281; COSMIC: COSV108138281;