rs45450893

Variant names:

• chr11-77205600-G-A
• rs45450893
• NM_000260.4:c.5619G>A

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.5619G>A​(p.Arg1873Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,613,468 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R1873R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (33 hom., cov: 32)
  • Exomes 𝑓: 0.022 (445 hom.)
• Consequence: MYO7A NM_000260.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.92
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-77205600-G-A is Benign according to our data. Variant chr11-77205600-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43293.
• BP7: Synonymous conserved (PhyloP=1.92 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0168 (2552/152296) while in subpopulation NFE AF = 0.027 (1833/68012). AF 95% confidence interval is 0.0259. There are 33 homozygotes in GnomAd4. There are 1207 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 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.5619G>A	p.Arg1873Arg	synonymous	Exon 40 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.5505G>A	p.Arg1835Arg	synonymous	Exon 40 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.5472G>A	p.Arg1824Arg	synonymous	Exon 41 of 50	NP_001356294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO7A	ENST00000409709.9	TSL:1 MANE Select	c.5619G>A	p.Arg1873Arg	synonymous	Exon 40 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.5505G>A	p.Arg1835Arg	synonymous	Exon 40 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.5472G>A	p.Arg1824Arg	synonymous	Exon 41 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2553 AN: 152178 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00476

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0205

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0154 AC: 3804 AN: 247660 AF XY: 0.0157

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00220

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.0209

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0220 AC: 32173 AN: 1461172 Hom.: 445 Cov.: 32 AF XY: 0.0217 AC XY: 15761 AN XY: 726870

African (AFR) AF: 0.00344 AC: 115 AN: 33472

American (AMR) AF: 0.0121 AC: 540 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26092

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00234 AC: 202 AN: 86164

European-Finnish (FIN) AF: 0.0203 AC: 1080 AN: 53156

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0262 AC: 29117 AN: 1111782

Other (OTH) AF: 0.0174 AC: 1050 AN: 60358

GnomAD4 genome AF: 0.0168 AC: 2552 AN: 152296 Hom.: 33 Cov.: 32 AF XY: 0.0162 AC XY: 1207 AN XY: 74480

African (AFR) AF: 0.00474 AC: 197 AN: 41548

American (AMR) AF: 0.0163 AC: 249 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.0205 AC: 218 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0270 AC: 1833 AN: 68012

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0227 Hom.: 69

Bravo AF: 0.0159

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0253

EpiControl AF: 0.0210

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.38
CADD	Benign	8.1
DANN	Benign	0.61
PhyloP100		1.9
Mutation Taster		=95/5	polymorphism (auto)

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: rs45450893; hg19: chr11-76916645;