rs201558076

chr1-216207438-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_206933.4(USH2A):c.3158-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,613,844 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (1 hom.)
• Consequence: USH2A NM_206933.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004707
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.108

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]

USH2A-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 1-216207438-T-C is Benign according to our data. Variant chr1-216207438-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 228212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4	c.3158-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000307340.8
USH2A-AS1	XR_922596.4	n.691+11513T>C		intron_variant, non_coding_transcript_variant
USH2A	NM_007123.6	c.3158-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8	c.3158-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_206933.4	P1
USH2A	ENST00000366942.3	c.3158-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
USH2A	ENST00000674083.1	c.3158-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 250944 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135622

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461634 Hom.: 1 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727106

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.000179

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: 0.00000270

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152210 Hom.: 1 Cov.: 32 AF XY: 0.000995 AC XY: 74 AN XY: 74408

Gnomad4 AFR AF: 0.00311

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.000971

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

c.3158-7A>G in intron 15 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.3% (28/10558) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs201558076). -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Usher syndrome type 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	9.5
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.076
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: rs201558076; hg19: chr1-216380780;