1-215782873-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_206933.4(USH2A):​c.10450C>G​(p.Arg3484Gly) 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. R3484Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

USH2A
NM_206933.4 missense

Scores

6
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.790
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.

PM1
In a domain Fibronectin type-III 19 (size 94) in uniprot entity USH2A_HUMAN there are 24 pathogenic changes around while only 8 benign (75%) in NM_206933.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.10450C>G p.Arg3484Gly missense_variant Exon 53 of 72 ENST00000307340.8 NP_996816.3 O75445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.10450C>G p.Arg3484Gly missense_variant Exon 53 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000674083.1 linkc.10450C>G p.Arg3484Gly missense_variant Exon 53 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.080
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
15
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.099
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.78
T
M_CAP
Uncertain
0.24
D
MetaRNN
Uncertain
0.50
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Uncertain
2.5
M
PrimateAI
Benign
0.20
T
PROVEAN
Uncertain
-2.9
D
REVEL
Benign
0.13
Sift
Benign
0.058
T
Sift4G
Uncertain
0.019
D
Polyphen
0.72
P
Vest4
0.53
MutPred
0.47
Loss of MoRF binding (P = 0.0232);
MVP
0.89
MPC
0.071
ClinPred
0.89
D
GERP RS
3.2
Varity_R
0.18
gMVP
0.67

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.

Other links and lift over

hg19: chr1-215956215; API