Variant rs111033439 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000307340.8(USH2A):c.10585G>T(p.Gly3529Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,460,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3529S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

USH2A
ENST00000307340.8 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.17

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000307340.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-215782738-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48353.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.10585G>T	p.Gly3529Cys	missense_variant, splice_region_variant	53/72	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.10585G>T	p.Gly3529Cys	missense_variant, splice_region_variant	53/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.10585G>T	p.Gly3529Cys	missense_variant, splice_region_variant	53/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250880

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135602

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460910

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726788

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.024

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.74

Loss of stability (P = 0.1938);

MVP

0.97

MPC

0.24

ClinPred

0.95

GERP RS

4.5

Varity_R

0.69

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: 0

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over