rs368341987

Variant names:

• chr11-77179843-G-A
• rs368341987
• NM_000260.4:c.2476G>A

Variant summary

Our verdict is Uncertain significance. The variant received -4 ACMG points: 4P and 8B. BA1 PM3 PP1 PP4

This summary comes from the ClinGen Evidence Repository: The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA180669/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00042 (2 hom., cov: 34)
  • Exomes 𝑓: 0.00071 (3 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:4 U:11 B:1 O:1
• Conservation: PhyloP100: 8.14
• Publications: 11 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: Uncertain_significance. The variant received -4 ACMG points.

• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.2476G>A	p.Ala826Thr	missense	Exon 21 of 49	NP_000251.3	Q13402-1
	MYO7A	NM_001127180.2		c.2476G>A	p.Ala826Thr	missense	Exon 21 of 49	NP_001120652.1	Q13402-2
	MYO7A	NM_001369365.1		c.2443G>A	p.Ala815Thr	missense	Exon 22 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.2476G>A	p.Ala826Thr	missense	Exon 21 of 49	ENSP00000386331.3	Q13402-1
	MYO7A	ENST00000458637.6	TSL:1	c.2476G>A	p.Ala826Thr	missense	Exon 21 of 49	ENSP00000392185.2	Q13402-2
	MYO7A	ENST00000409619.6	TSL:1	c.2443G>A	p.Ala815Thr	missense	Exon 22 of 50	ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152256 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00661

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00121 AC: 170 AN: 139996 AF XY: 0.00162

Gnomad AFR exome AF: 0.000292

Gnomad AMR exome AF: 0.0000816

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000939

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000711 AC: 989 AN: 1390456 Hom.: 3 Cov.: 31 AF XY: 0.000869 AC XY: 596 AN XY: 686182

African (AFR) AF: 0.000158 AC: 5 AN: 31590

American (AMR) AF: 0.000112 AC: 4 AN: 35732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.0000559 AC: 2 AN: 35748

South Asian (SAS) AF: 0.00597 AC: 473 AN: 79186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41046

Middle Eastern (MID) AF: 0.000573 AC: 3 AN: 5236

European-Non Finnish (NFE) AF: 0.000427 AC: 461 AN: 1078864

Other (OTH) AF: 0.000708 AC: 41 AN: 57886

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152374 Hom.: 2 Cov.: 34 AF XY: 0.000523 AC XY: 39 AN XY: 74512

African (AFR) AF: 0.0000481 AC: 2 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00662 AC: 32 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000419 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.000129 AC: 1

ExAC AF: 0.000974 AC: 78

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	3	-	not provided (4)
1	2	-	Usher syndrome type 1 (3)
1	1	-	Autosomal recessive nonsyndromic hearing loss 2 (2)
-	2	-	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 11 (1)
1	-	-	MYO7A-related disorder (1)
-	1	-	Usher syndrome (1)
-	1	-	Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 (2)
-	1	-	Usher syndrome type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	1.0	L
PhyloP100		8.1
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.65	P
Vest4		0.50
MVP		0.92
MPC		0.15
ClinPred		0.059	T
GERP RS		4.5
PromoterAI		-0.036	Neutral
Varity_R		0.51
gMVP		0.57
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs368341987; hg19: chr11-76890889;