21-39410304-T-C

Position:

• chr21-39410304-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152505.4(LCA5L):​c.1124A>G​(p.Gln375Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LCA5L NM_152505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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:):

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2909242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCA5L	NM_152505.4	c.1124A>G	p.Gln375Arg	missense_variant	9/11	ENST00000288350.8	NP_689718.1
GET1-SH3BGR	NR_146618.2	n.826-540T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCA5L	ENST00000288350.8	c.1124A>G	p.Gln375Arg	missense_variant	9/11	5	NM_152505.4	ENSP00000288350	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.1124A>G (p.Q375R) alteration is located in exon 8 (coding exon 5) of the LCA5L gene. This alteration results from a A to G substitution at nucleotide position 1124, causing the glutamine (Q) at amino acid position 375 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0036	T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.63	T;.;.
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	0.61	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.099	T;T;T
Sift4G	Uncertain	0.042	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.33
MutPred		0.15		Loss of ubiquitination at K379 (P = 0.0157);Loss of ubiquitination at K379 (P = 0.0157);Loss of ubiquitination at K379 (P = 0.0157);
MVP		0.76
MPC		0.39
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.11

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: chr21-40782230;