rs34477144

Variant names:

• chr11-77156699-G-A
• rs34477144
• NM_000260.4:c.510G>A
• MYO7A p.Leu170Leu

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.510G>A​(p.Leu170Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00175 in 1,614,014 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO7A is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0015 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (20 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: 4.04
• Publications: 3 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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: Ambry Genetics, 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

Specifications for MYO7A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 11-77156699-G-A is Benign according to our data. Variant chr11-77156699-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43272.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0015 (229/152324) while in subpopulation SAS AF = 0.00291 (14/4818). AF 95% confidence interval is 0.00176. There are 3 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD 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.510G>A	p.Leu170Leu	synonymous	Exon 6 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.510G>A	p.Leu170Leu	synonymous	Exon 6 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.477G>A	p.Leu159Leu	synonymous	Exon 7 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.510G>A	p.Leu170Leu	synonymous	Exon 6 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.510G>A	p.Leu170Leu	synonymous	Exon 6 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.477G>A	p.Leu159Leu	synonymous	Exon 7 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00266 AC: 664 AN: 249240 AF XY: 0.00292

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.00446

GnomAD4 exome AF: 0.00178 AC: 2599 AN: 1461690 Hom.: 20 Cov.: 32 AF XY: 0.00194 AC XY: 1407 AN XY: 727130

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00295 AC: 132 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 294 AN: 26136

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

South Asian (SAS) AF: 0.00394 AC: 340 AN: 86256

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53388

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5766

European-Non Finnish (NFE) AF: 0.00124 AC: 1377 AN: 1111868

Other (OTH) AF: 0.00353 AC: 213 AN: 60374

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74484

African (AFR) AF: 0.000481 AC: 20 AN: 41576

American (AMR) AF: 0.00170 AC: 26 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00291 AC: 14 AN: 4818

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68040

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00262 Hom.: 1

Bravo AF: 0.00178

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	1	1	Usher syndrome type 1 (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
-	1	-	Autosomal recessive nonsyndromic hearing loss 2 (1)
-	-	1	MYO7A-related disorder (1)
-	-	1	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		4.0
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34477144;

hg19: chr11-76867745;