21-39410003-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152505.4(LCA5L):c.1258G>A(p.Glu420Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000203 in 1,573,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

LCA5L
NM_152505.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

Publications

1 publications found

Variant links:

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]

LCA5L links:

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-SH3BGR links:

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]

GET1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22270888).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LCA5L	NM_152505.4	MANE Select	c.1258G>A	p.Glu420Lys	missense	Exon 10 of 11	NP_689718.1	O95447
LCA5L	NM_001384285.1		c.1258G>A	p.Glu420Lys	missense	Exon 9 of 10	NP_001371214.1	O95447
LCA5L	NM_001384286.1		c.1258G>A	p.Glu420Lys	missense	Exon 9 of 10	NP_001371215.1	O95447

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LCA5L	ENST00000288350.8	TSL:5 MANE Select	c.1258G>A	p.Glu420Lys	missense	Exon 10 of 11	ENSP00000288350.3	O95447
LCA5L	ENST00000358268.6	TSL:1	c.1258G>A	p.Glu420Lys	missense	Exon 9 of 10	ENSP00000351008.2	O95447
LCA5L	ENST00000380671.6	TSL:1	c.1258G>A	p.Glu420Lys	missense	Exon 6 of 7	ENSP00000370046.2	O95447

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000162

AC:

AN:

247022

AF XY:

0.0000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000183

AC:

AN:

1421778

Hom.:

Cov.:

AF XY:

0.0000226

AC XY:

AN XY:

709296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32494

American (AMR)

AF:

0.00

AC:

AN:

43648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25830

East Asian (EAS)

AF:

0.00

AC:

AN:

39458

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.0000185

AC:

AN:

1078358

Other (OTH)

AF:

0.0000847

AC:

AN:

59054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.046

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.80

M_CAP

Benign

0.013

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.9

PhyloP100

3.9

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.8

REVEL

Benign

0.15

Sift

Benign

0.074

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.21

MutPred

0.18

Gain of methylation at E420 (P = 0.0067)

MVP

0.74

MPC

0.42

ClinPred

0.96

GERP RS

4.5

Varity_R

0.40

gMVP

0.24

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over