rs35429535

Variant names:

• chr11-77172804-G-A
• rs35429535
• NM_000260.4:c.1854G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000260.4(MYO7A):​c.1854G>A​(p.Leu618Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00386 in 1,556,814 control chromosomes in the GnomAD database, including 18 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 0.0026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (17 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 4.54
• Publications: 2 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-77172804-G-A is Benign according to our data. Variant chr11-77172804-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43161.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00265 (403/152342) while in subpopulation NFE AF = 0.005 (340/68024). AF 95% confidence interval is 0.00456. There are 1 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.1854G>A	p.Leu618Leu	synonymous	Exon 16 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.1854G>A	p.Leu618Leu	synonymous	Exon 16 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.1821G>A	p.Leu607Leu	synonymous	Exon 17 of 50	NP_001356294.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.1854G>A	p.Leu618Leu	synonymous	Exon 16 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.1854G>A	p.Leu618Leu	synonymous	Exon 16 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.1821G>A	p.Leu607Leu	synonymous	Exon 17 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00217 AC: 351 AN: 161750 AF XY: 0.00205

Gnomad AFR exome AF: 0.000602

Gnomad AMR exome AF: 0.000793

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00471

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00399 AC: 5608 AN: 1404472 Hom.: 17 Cov.: 31 AF XY: 0.00377 AC XY: 2612 AN XY: 693242

African (AFR) AF: 0.000692 AC: 22 AN: 31774

American (AMR) AF: 0.00102 AC: 37 AN: 36390

Ashkenazi Jewish (ASJ) AF: 0.0000793 AC: 2 AN: 25224

East Asian (EAS) AF: 0.00 AC: 0 AN: 36030

South Asian (SAS) AF: 0.000252 AC: 20 AN: 79392

European-Finnish (FIN) AF: 0.000527 AC: 26 AN: 49366

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5700

European-Non Finnish (NFE) AF: 0.00490 AC: 5304 AN: 1082344

Other (OTH) AF: 0.00335 AC: 195 AN: 58252

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00223 AC XY: 166 AN XY: 74496

African (AFR) AF: 0.000721 AC: 30 AN: 41586

American (AMR) AF: 0.00137 AC: 21 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00500 AC: 340 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00328 Hom.: 0

Bravo AF: 0.00250

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (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	-0.34
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		4.5
Mutation Taster		=78/22	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: rs35429535; hg19: chr11-76883850;