21-39405910-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152505.4(LCA5L):c.1985C>T(p.Thr662Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,597,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: LCA5L NM_152505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03146246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCA5L	NM_152505.4	c.1985C>T	p.Thr662Ile	missense_variant	11/11	ENST00000288350.8
GET1-SH3BGR	NR_146618.2	n.511-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCA5L	ENST00000288350.8	c.1985C>T	p.Thr662Ile	missense_variant	11/11	5	NM_152505.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152122 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000154 AC: 38 AN: 246138 Hom.: 0 AF XY: 0.000150 AC XY: 20 AN XY: 133630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.000719

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000259

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000245 AC: 354 AN: 1445028 Hom.: 1 Cov.: 28 AF XY: 0.000224 AC XY: 161 AN XY: 719326

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000464

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000284

Gnomad4 OTH exome AF: 0.000201

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74432

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000244 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000206 AC: 25

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

Dec 17, 2023

The c.1985C>T (p.T662I) alteration is located in exon 10 (coding exon 7) of the LCA5L gene. This alteration results from a C to T substitution at nucleotide position 1985, causing the threonine (T) at amino acid position 662 to be replaced by an isoleucine (I). 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	0.16
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0046	T;T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.58	T;.;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.065	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.11
MVP		0.38
MPC		0.081
ClinPred		0.031	T
GERP RS		3.1
Varity_R		0.049
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs200492515; hg19: chr21-40777836;