21-39406072-A-T

Variant names:

• chr21-39406072-A-T
• NM_152505.4:c.1823T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152505.4(LCA5L):​c.1823T>A​(p.Val608Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LCA5L NM_152505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19186085).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCA5L	NM_152505.4	c.1823T>A	p.Val608Asp	missense_variant	Exon 11 of 11	ENST00000288350.8	NP_689718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCA5L	ENST00000288350.8	c.1823T>A	p.Val608Asp	missense_variant	Exon 11 of 11	5	NM_152505.4	ENSP00000288350.3
GET1-SH3BGR	ENST00000647779.1	c.336+14236A>T		intron_variant	Intron 3 of 8			ENSP00000497977.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1823T>A (p.V608D) alteration is located in exon 10 (coding exon 7) of the LCA5L gene. This alteration results from a T to A substitution at nucleotide position 1823, causing the valine (V) at amino acid position 608 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.0086	T;T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.61	T;.;.
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.0	M;M;M
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.96	D;D;D
Vest4		0.40
MutPred		0.17		Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);
MVP		0.61
MPC		0.44
ClinPred		0.50	D
GERP RS		2.3
Varity_R		0.36
gMVP		0.23

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-40777998;