rs397518004

Positions:

• chr1-216289317-G-A
• chr1-216289317-G-C
• chr1-216289317-G-T

Variant summary

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

The ENST00000307340.8(USH2A):​c.1934C>T​(p.Thr645Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T645T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: USH2A ENST00000307340.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.223

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 domain Laminin EGF-like 3 (size 52) in uniprot entity USH2A_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in ENST00000307340.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095002025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.1934C>T	p.Thr645Ile	missense_variant	11/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1934C>T	p.Thr645Ile	missense_variant	11/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1934C>T	p.Thr645Ile	missense_variant	11/72	1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.1934C>T	p.Thr645Ile	missense_variant	11/21	1		ENSP00000355909
USH2A	ENST00000674083.1	c.1934C>T	p.Thr645Ile	missense_variant	11/73			ENSP00000501296

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 14, 2013

Variant classified as Uncertain Significance - Favor Benign. The Thr645Ile varia nt in USH2A has not been reported in affected individuals or in large population studies. This amino acid is not conserved in mammals, including primates, and c omputational analyses (biochemical amino acid properties, conservation, AlignGVG D, PolyPhen2, and SIFT) suggest that the Thr645Ile variant may not impact the pr otein, though this information is not predictive enough to rule out pathogenicit y. In summary, additional information is needed to determine the clinical signif icance of this variant; however, we would lean towards a more likely benign role . -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.20	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.54	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.042
Sift	Benign	0.20	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.065	B;B
Vest4		0.18
MutPred		0.48		Loss of disorder (P = 0.0856);Loss of disorder (P = 0.0856);
MVP		0.77
MPC		0.032
ClinPred		0.065	T
GERP RS		0.35
Varity_R		0.046
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397518004; hg19: chr1-216462659;