dbSNP rs483353055: USH2A:p.Ser1136Ile (chr1-216200031-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_206933.4(USH2A):c.3407G>T(p.Ser1136Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S1136N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.84

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:

USH2A-AS1 (HGNC:40606): (USH2A antisense RNA 1)

USH2A-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a domain Fibronectin type-III 1 (size 88) in uniprot entity USH2A_HUMAN there are 16 pathogenic changes around while only 5 benign (76%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-216200031-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 133312.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.3407G>T	p.Ser1136Ile	missense_variant	Exon 17 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.3407G>T	p.Ser1136Ile	missense_variant	Exon 17 of 72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.3407G>T	p.Ser1136Ile	missense_variant	Exon 17 of 21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.3407G>T	p.Ser1136Ile	missense_variant	Exon 17 of 73			ENSP00000501296.1	O75445-3
USH2A-AS1	ENST00000420867.1 link	n.363-3999C>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

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:

8.99e-7

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

0.87

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.67

Loss of catalytic residue at S1136 (P = 0.005);Loss of catalytic residue at S1136 (P = 0.005);

MVP

0.97

MPC

0.25

ClinPred

1.0

GERP RS

6.0

Varity_R

0.79

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over