rs138543813

Positions:

• chr1-215798994-C-G
• chr1-215798994-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_206933.4(USH2A):​c.9871G>C​(p.Gly3291Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. G3291S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: USH2A NM_206933.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.807

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14110687).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.9871G>C	p.Gly3291Arg	missense_variant	50/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.9871G>C	p.Gly3291Arg	missense_variant	50/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.9871G>C	p.Gly3291Arg	missense_variant	50/73

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251216 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135760

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.44	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.26		Loss of ubiquitination at K3293 (P = 0.0396);
MVP		0.57
MPC		0.034
ClinPred		0.056	T
GERP RS		0.40
Varity_R		0.058
gMVP		0.23

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

Other links and lift over

dbSNP: rs138543813; hg19: chr1-215972336;