rs74329863

Positions:

• chr1-216327586-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_206933.4(USH2A):​c.848+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,613,076 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (38 hom.)
• Consequence: USH2A NM_206933.4 splice_region, intron
• Scores: Splicing: ADA: 0.4219
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.301

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 1-216327586-C-G is Benign according to our data. Variant chr1-216327586-C-G is described in ClinVar as [Benign]. Clinvar id is 48602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216327586-C-G is described in Lovd as [Benign]. Variant chr1-216327586-C-G is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00642 (978/152254) while in subpopulation EAS AF= 0.0361 (187/5186). AF 95% confidence interval is 0.0318. There are 3 homozygotes in gnomad4. There are 462 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4	c.848+5G>C		splice_region_variant, intron_variant		ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6	c.848+5G>C		splice_region_variant, intron_variant			NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.848+5G>C		splice_region_variant, intron_variant		1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000366942.3	c.848+5G>C		splice_region_variant, intron_variant		1		ENSP00000355909.3
USH2A	ENST00000674083.1	c.848+5G>C		splice_region_variant, intron_variant				ENSP00000501296.1

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 978 AN: 152136 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00399 AC: 1000 AN: 250884 Hom.: 6 AF XY: 0.00341 AC XY: 463 AN XY: 135584

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0314

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00171 AC: 2504 AN: 1460822 Hom.: 38 Cov.: 31 AF XY: 0.00161 AC XY: 1173 AN XY: 726732

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.000575

Gnomad4 EAS exome AF: 0.0309

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.00563

GnomAD4 genome AF: 0.00642 AC: 978 AN: 152254 Hom.: 3 Cov.: 32 AF XY: 0.00621 AC XY: 462 AN XY: 74432

Gnomad4 AFR AF: 0.0172

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0361

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00198 Hom.: 1

Bravo AF: 0.00755

Asia WGS AF: 0.0250 AC: 86 AN: 3476

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 29625443) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	USH2A: BP4, BS1, BS2 -

Usher syndrome type 2A Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 01, 2011

848+5G>C in intron 5 of USH2A: This variant is not expected to have clinical sig nificance because it has been identified with a frequency of 3.4% in the East As ian population (208 chromosomes) and a frequency of 2.5% in the West African pop ulation (118 chromosomes) (rs74329863). In addition, this variant has been ident ified in 2/15 (13/3%) of Asian individuals tested by our laboratory, one of whic h is homozygous for a pathogenic MYO7A variant. Furthermore, the 848+5G>C varian t is located in the 5' splice region but does not affect the invariant +1 and +2 positions. -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

Retinitis pigmentosa 39 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.42
dbscSNV1_RF	Benign	0.42
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: rs74329863; hg19: chr1-216500928;