chr11-77213021-G-A

Variant names:

• chr11-77213021-G-A
• rs1132036
• NM_000260.4:c.6424G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.6424G>A​(p.Asp2142Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00542 in 1,580,324 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2142E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (217 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (173 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.37
• Publications: 9 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 (MetaRNN=0.002082765).
• BP6: Variant 11-77213021-G-A is Benign according to our data. Variant chr11-77213021-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

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.6424G>A	p.Asp2142Asn	missense	Exon 47 of 49	NP_000251.3
	MYO7A	NM_001127180.2		c.6304G>A	p.Asp2102Asn	missense	Exon 47 of 49	NP_001120652.1
	MYO7A	NM_001369365.1		c.6277G>A	p.Asp2093Asn	missense	Exon 48 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.6424G>A	p.Asp2142Asn	missense	Exon 47 of 49	ENSP00000386331.3
	MYO7A	ENST00000458637.6	TSL:1	c.6304G>A	p.Asp2102Asn	missense	Exon 47 of 49	ENSP00000392185.2
	MYO7A	ENST00000409619.6	TSL:1	c.6277G>A	p.Asp2093Asn	missense	Exon 48 of 50	ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.0281 AC: 4270 AN: 151964 Hom.: 214 Cov.: 31

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00709 AC: 1388 AN: 195658 AF XY: 0.00554

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00544

GnomAD4 exome AF: 0.00298 AC: 4263 AN: 1428242 Hom.: 173 Cov.: 30 AF XY: 0.00264 AC XY: 1865 AN XY: 706864

African (AFR) AF: 0.101 AC: 3322 AN: 32738

American (AMR) AF: 0.00569 AC: 227 AN: 39888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38296

South Asian (SAS) AF: 0.000370 AC: 30 AN: 81106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51334

Middle Eastern (MID) AF: 0.00576 AC: 33 AN: 5732

European-Non Finnish (NFE) AF: 0.000257 AC: 281 AN: 1094358

Other (OTH) AF: 0.00623 AC: 369 AN: 59266

GnomAD4 genome AF: 0.0282 AC: 4295 AN: 152082 Hom.: 217 Cov.: 31 AF XY: 0.0283 AC XY: 2102 AN XY: 74330

African (AFR) AF: 0.0978 AC: 4054 AN: 41452

American (AMR) AF: 0.0107 AC: 164 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 67988

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0114 Hom.: 212

Bravo AF: 0.0321

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0791 AC: 312

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00756 AC: 907

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.040	N
PhyloP100		5.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.19
Sift	Benign	0.42	T
Sift4G	Benign	0.36	T
Polyphen		0.33	B
Vest4		0.46
MVP		0.86
MPC		0.37
ClinPred		0.016	T
GERP RS		3.8
Varity_R		0.22
gMVP		0.69
Mutation Taster		=86/14	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: rs1132036; hg19: chr11-76924066; COSMIC: COSV60020045; COSMIC: COSV60020045;