1-215782813-G-A

Position:

• chr1-215782813-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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 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
USH2A	NM_206933.4	c.10510C>T	p.Pro3504Ser	missense_variant	53/72	ENST00000307340.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.10510C>T	p.Pro3504Ser	missense_variant	53/72	1	NM_206933.4	P1
USH2A	ENST00000674083.1	c.10510C>T	p.Pro3504Ser	missense_variant	53/73

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

Other links and lift over

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