21-39406558-C-T

Variant names:

• chr21-39406558-C-T
• rs372283171
• NM_152505.4:c.1337G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152505.4(LCA5L):​c.1337G>A​(p.Gly446Glu) 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. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G446A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LCA5L NM_152505.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.129
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04493004).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152505.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5L	NM_152505.4	MANE Select	c.1337G>A	p.Gly446Glu	missense	Exon 11 of 11	NP_689718.1	O95447
	LCA5L	NM_001384285.1		c.1337G>A	p.Gly446Glu	missense	Exon 10 of 10	NP_001371214.1	O95447
	LCA5L	NM_001384286.1		c.1337G>A	p.Gly446Glu	missense	Exon 10 of 10	NP_001371215.1	O95447

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5L	ENST00000288350.8	TSL:5 MANE Select	c.1337G>A	p.Gly446Glu	missense	Exon 11 of 11	ENSP00000288350.3	O95447
	LCA5L	ENST00000358268.6	TSL:1	c.1337G>A	p.Gly446Glu	missense	Exon 10 of 10	ENSP00000351008.2	O95447
	LCA5L	ENST00000380671.6	TSL:1	c.1337G>A	p.Gly446Glu	missense	Exon 7 of 7	ENSP00000370046.2	O95447

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.0
DANN	Benign	0.43
DEOGEN2	Benign	0.00069	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.13
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.035
Sift	Benign	0.79	T
Sift4G	Benign	0.32	T
Polyphen		0.0080	B
Vest4		0.045
MutPred		0.29		Gain of ubiquitination at K451 (P = 0.0872)
MVP		0.16
MPC		0.099
ClinPred		0.025	T
GERP RS		-0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.037
Mutation Taster		=99/1	polymorphism

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: rs372283171; hg19: chr21-40778484; COSMIC: COSV105165278; COSMIC: COSV105165278;