21-39410059-T-C

Variant summary

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

The NM_152505.4(LCA5L):c.1202A>G(p.Lys401Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,611,650 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: LCA5L NM_152505.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706

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=0.017074227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCA5L	NM_152505.4	c.1202A>G	p.Lys401Arg	missense_variant	10/11	ENST00000288350.8
GET1-SH3BGR	NR_146618.2	n.826-785T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCA5L	ENST00000288350.8	c.1202A>G	p.Lys401Arg	missense_variant	10/11	5	NM_152505.4	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000280 AC: 70 AN: 250204 Hom.: 0 AF XY: 0.000281 AC XY: 38 AN XY: 135180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1459308 Hom.: 0 Cov.: 29 AF XY: 0.000178 AC XY: 129 AN XY: 726016

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000239 AC: 29

EpiCase AF: 0.000327

EpiControl AF: 0.000415

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

Sep 27, 2021

The c.1202A>G (p.K401R) alteration is located in exon 9 (coding exon 6) of the LCA5L gene. This alteration results from a A to G substitution at nucleotide position 1202, causing the lysine (K) at amino acid position 401 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	0.094
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0016	T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.54	T;.;.
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	0.88	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.36	B;B;B
Vest4		0.11
MVP		0.32
MPC		0.13
ClinPred		0.032	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.065

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: rs138224767; hg19: chr21-40781985;