rs727503723

Positions:

chr1-215993027-ATAT-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_206933.4(USH2A):c.6795_6797del(p.Glu2265_Tyr2266delinsAsp) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000149 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

USH2A
NM_206933.4 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 3.65

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a domain Fibronectin type-III 9 (size 87) in uniprot entity USH2A_HUMAN there are 25 pathogenic changes around while only 7 benign (78%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_206933.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 1-215993027-ATAT-A is Pathogenic according to our data. Variant chr1-215993027-ATAT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 166478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215993027-ATAT-A is described in Lovd as [Pathogenic]. Variant chr1-215993027-ATAT-A is described in Lovd as [Pathogenic]. Variant chr1-215993027-ATAT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.6795_6797del	p.Glu2265_Tyr2266delinsAsp	inframe_deletion	35/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.6795_6797del	p.Glu2265_Tyr2266delinsAsp	inframe_deletion	35/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.6795_6797del	p.Glu2265_Tyr2266delinsAsp	inframe_deletion	35/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251138

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461794

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This variant, c.6795_6797del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the USH2A protein (p.Glu2265_Tyr2266delinsAsp). This variant is present in population databases (rs727503723, gnomAD 0.002%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22135276, 26667666, 27957503). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166478). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Retinitis pigmentosa 39

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 18, 2017

proposed classification - variant undergoing re-assessment, contact laboratory -

Usher syndrome type 2A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 04, 2023

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over