rs200372118

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_206933.4(USH2A):​c.10510C>T​(p.Pro3504Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P3504A) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Consequence

USH2A
NM_206933.4 missense

Scores

1
7
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.12
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
USH2ANM_206933.4 linkuse as main transcriptc.10510C>T p.Pro3504Ser missense_variant 53/72 ENST00000307340.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.10510C>T p.Pro3504Ser missense_variant 53/721 NM_206933.4 P1O75445-1
USH2AENST00000674083.1 linkuse as main transcriptc.10510C>T p.Pro3504Ser missense_variant 53/73 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T
Eigen
Benign
0.091
Eigen_PC
Benign
-0.00091
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.80
T
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-0.79
T
MutationAssessor
Pathogenic
3.3
M
MutationTaster
Benign
0.99
D;D
PrimateAI
Benign
0.29
T
PROVEAN
Uncertain
-4.3
D
REVEL
Benign
0.17
Sift
Uncertain
0.026
D
Sift4G
Uncertain
0.018
D
Polyphen
0.80
P
Vest4
0.45
MutPred
0.48
Loss of catalytic residue at P3504 (P = 0.003);
MVP
0.89
MPC
0.061
ClinPred
0.96
D
GERP RS
3.3
Varity_R
0.082
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs200372118; hg19: chr1-215956155; COSMIC: COSV105134466; API