chr21-39428445-C-T

Variant names:

• chr21-39428445-C-T
• rs2837029
• NM_152505.4:c.49G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152505.4(LCA5L):​c.49G>A​(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,608,006 control chromosomes in the GnomAD database, including 36,533 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (5070 hom., cov: 27)
  • Exomes 𝑓: 0.20 (31463 hom.)
• Consequence: LCA5L NM_152505.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 28 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029594898).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5L	NM_152505.4	MANE Select	c.49G>A	p.Gly17Ser	missense	Exon 5 of 11	NP_689718.1
	LCA5L	NM_001384285.1		c.49G>A	p.Gly17Ser	missense	Exon 4 of 10	NP_001371214.1
	LCA5L	NM_001384286.1		c.49G>A	p.Gly17Ser	missense	Exon 4 of 10	NP_001371215.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCA5L	ENST00000288350.8	TSL:5 MANE Select	c.49G>A	p.Gly17Ser	missense	Exon 5 of 11	ENSP00000288350.3
	LCA5L	ENST00000358268.6	TSL:1	c.49G>A	p.Gly17Ser	missense	Exon 4 of 10	ENSP00000351008.2
	LCA5L	ENST00000380671.6	TSL:1	c.49G>A	p.Gly17Ser	missense	Exon 1 of 7	ENSP00000370046.2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36124 AN: 149882 Hom.: 5059 Cov.: 27

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0253

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.227

GnomAD2 exomes AF: 0.185 AC: 46282 AN: 249560 AF XY: 0.188

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.113

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.0187

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.200 AC: 292106 AN: 1458008 Hom.: 31463 Cov.: 32 AF XY: 0.200 AC XY: 145356 AN XY: 725402

African (AFR) AF: 0.387 AC: 12925 AN: 33398

American (AMR) AF: 0.121 AC: 5355 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5732 AN: 26078

East Asian (EAS) AF: 0.0212 AC: 831 AN: 39178

South Asian (SAS) AF: 0.201 AC: 17273 AN: 85774

European-Finnish (FIN) AF: 0.133 AC: 7099 AN: 53310

Middle Eastern (MID) AF: 0.321 AC: 1848 AN: 5756

European-Non Finnish (NFE) AF: 0.206 AC: 228252 AN: 1109854

Other (OTH) AF: 0.212 AC: 12791 AN: 60234

GnomAD4 genome AF: 0.241 AC: 36169 AN: 149998 Hom.: 5070 Cov.: 27 AF XY: 0.233 AC XY: 17055 AN XY: 73076

African (AFR) AF: 0.388 AC: 15863 AN: 40844

American (AMR) AF: 0.173 AC: 2597 AN: 14990

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3462

East Asian (EAS) AF: 0.0252 AC: 126 AN: 5004

South Asian (SAS) AF: 0.182 AC: 860 AN: 4726

European-Finnish (FIN) AF: 0.132 AC: 1332 AN: 10124

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.205 AC: 13883 AN: 67596

Other (OTH) AF: 0.228 AC: 470 AN: 2064

Alfa AF: 0.216 Hom.: 17585

Bravo AF: 0.247

TwinsUK AF: 0.204 AC: 756

ALSPAC AF: 0.210 AC: 810

ESP6500AA AF: 0.395 AC: 1741

ESP6500EA AF: 0.198 AC: 1703

ExAC AF: 0.193 AC: 23447

Asia WGS AF: 0.132 AC: 461 AN: 3476

EpiCase AF: 0.224

EpiControl AF: 0.227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.013
DANN	Benign	0.58
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-1.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.0010	B
Vest4		0.018
MPC		0.068
ClinPred		0.0022	T
GERP RS		-3.1
PromoterAI		0.012	Neutral
Varity_R		0.038
gMVP		0.083
Mutation Taster		=100/0	polymorphism (auto)

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: rs2837029; hg19: chr21-40800371; COSMIC: COSV55747675; COSMIC: COSV55747675;