1-216190379-AAAAGAAAGAAAG-AAAAGAAAG

Position:

• chr1-216190379-AAAAGAAAGAAAG-AAAAGAAAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000307340.8(USH2A):​c.4252-16_4252-13del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00702 in 1,597,562 control chromosomes in the GnomAD database, including 524 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (282 hom., cov: 31)
  • Exomes 𝑓: 0.0042 (242 hom.)
• Consequence: USH2A ENST00000307340.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.46

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 1-216190379-AAAAG-A is Benign according to our data. Variant chr1-216190379-AAAAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 178671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216190379-AAAAG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.4252-16_4252-13del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.4252-16_4252-13del		splice_polypyrimidine_tract_variant, intron_variant			NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.4252-16_4252-13del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_206933.4	ENSP00000305941	P1
USH2A	ENST00000366942.3	c.4252-16_4252-13del		splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000355909
USH2A	ENST00000674083.1	c.4252-16_4252-13del		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000501296

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5103 AN: 151604 Hom.: 277 Cov.: 31

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.00955 AC: 2339 AN: 244842 Hom.: 115 AF XY: 0.00742 AC XY: 983 AN XY: 132502

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.00693

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.000501

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.000935

Gnomad OTH exome AF: 0.00518

GnomAD4 exome AF: 0.00421 AC: 6090 AN: 1445842 Hom.: 242 AF XY: 0.00379 AC XY: 2728 AN XY: 719300

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.00807

Gnomad4 ASJ exome AF: 0.000661

Gnomad4 EAS exome AF: 0.000771

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.00110

Gnomad4 NFE exome AF: 0.000765

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0338 AC: 5130 AN: 151720 Hom.: 282 Cov.: 31 AF XY: 0.0323 AC XY: 2395 AN XY: 74142

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.0256

Bravo AF: 0.0377

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 17, 2015	4252-16_4252-13delCTTT in Intron 19 of USH2A: This variant is not expected to h ave clinical significance because it does not alter the splice consensus sequenc e and it has been identified in 10.9% (466/4264) African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2018	- -

Retinitis Pigmentosa, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Retinitis pigmentosa 39 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Retinitis pigmentosa-deafness syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Usher syndrome type 2A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs372388546; hg19: chr1-216363721;