rs1553250774

Variant names:

• chr1-216325306-T-C
• rs1553250774
• NM_206933.4:c.1142A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_206933.4(USH2A):​c.1142A>G​(p.Gln381Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: USH2A NM_206933.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.72

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 109 pathogenic changes around while only 17 benign (87%) in NM_206933.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.1142A>G	p.Gln381Arg	missense_variant, splice_region_variant	Exon 6 of 72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.1142A>G	p.Gln381Arg	missense_variant, splice_region_variant	Exon 6 of 21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.1142A>G	p.Gln381Arg	missense_variant, splice_region_variant	Exon 6 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.1142A>G	p.Gln381Arg	missense_variant, splice_region_variant	Exon 6 of 21	1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.1142A>G	p.Gln381Arg	missense_variant, splice_region_variant	Exon 6 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461304 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726948

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Uncertain:1

May 31, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 381 of the USH2A protein (p.Gln381Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with inherited retinal dystrophy and/or retinitis pigmentosa (PMID: 24938718; Invitae). ClinVar contains an entry for this variant (Variation ID: 558605). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Retinitis pigmentosa 39 Uncertain:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2A Uncertain:1

Nov 04, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.3	M;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0040	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.88
MutPred		0.60		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.95
MPC		0.23
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553250774; hg19: chr1-216498648;