rs2837022

Variant names:

• chr21-39424825-T-C
• rs2837022
• NM_152505.4:c.323-1335A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152505.4(LCA5L):​c.323-1335A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.09 in 152,292 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.090 (799 hom., cov: 32)
• Consequence: LCA5L NM_152505.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.407
• Publications: 7 publications found

Genes affected

LCA5L (HGNC:1255): (lebercilin LCA5 like) Predicted to be involved in intraciliary transport. Predicted to be active in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

GET1-SH3BGR (HGNC:54635): (GET1-SH3BGR readthrough) This locus represents naturally occurring readthrough transcription between the neighboring WRB (tryptophan rich basic protein) and SH3BGR (SH3 domain binding glutamate-rich protein) genes on chromosome 21. Readthrough transcripts may encode fusion proteins that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

GET1 (HGNC:12790): (guided entry of tail-anchored proteins factor 1) This gene is located in the candidate region for congenital heart disease (CHD) in Down syndrome (DS). It encodes a basic protein that functions as a receptor that promotes insertion of tail-anchored proteins in the endoplasmic reticulum membrane. This gene is located at a maternally-methylated differentially methylated region (DMR); however, its transcription may be biallelic, not imprinted. Alternative splicing results in different transcript variants. A pseudogene has been defined on chromosome 4. [provided by RefSeq, Apr 2017]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCA5L	NM_152505.4	c.323-1335A>G		intron_variant	Intron 5 of 10	ENST00000288350.8	NP_689718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCA5L	ENST00000288350.8	c.323-1335A>G		intron_variant	Intron 5 of 10	5	NM_152505.4	ENSP00000288350.3
GET1-SH3BGR	ENST00000647779.1	c.336+32989T>C		intron_variant	Intron 3 of 8			ENSP00000497977.1

Frequencies

GnomAD3 genomes AF: 0.0900 AC: 13703 AN: 152174 Hom.: 799 Cov.: 32

Gnomad AFR AF: 0.0294

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0832

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0861

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.0956

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0900 AC: 13701 AN: 152292 Hom.: 799 Cov.: 32 AF XY: 0.0883 AC XY: 6573 AN XY: 74458

African (AFR) AF: 0.0293 AC: 1217 AN: 41582

American (AMR) AF: 0.0830 AC: 1269 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 472 AN: 3470

East Asian (EAS) AF: 0.0235 AC: 122 AN: 5188

South Asian (SAS) AF: 0.132 AC: 636 AN: 4830

European-Finnish (FIN) AF: 0.0861 AC: 913 AN: 10598

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8736 AN: 68016

Other (OTH) AF: 0.0974 AC: 206 AN: 2114

Alfa AF: 0.120 Hom.: 1955

Bravo AF: 0.0844

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.9
DANN	Benign	0.77
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2837022; hg19: chr21-40796751;