rs3741792

Positions:

• chr12-12117026-G-A
• chr12-12117026-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000261349.9(LRP6):​c.*4100C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.048 in 152,186 control chromosomes in the GnomAD database, including 251 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.048 (251 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: LRP6 ENST00000261349.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.378

Genes affected

LRP6 (HGNC:6698): (LDL receptor related protein 6) This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.[provided by RefSeq, Dec 2009]

BCL2L14 (HGNC:16657): (BCL2 like 14) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. Overexpression of this gene has been shown to induce apoptosis in cells. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRP6	NM_002336.3	c.*4100C>T		3_prime_UTR_variant	23/23	ENST00000261349.9	NP_002327.2
LRP6	XM_047428844.1	c.*4100C>T		3_prime_UTR_variant	21/21		XP_047284800.1
LRP6	NR_182264.1	n.7530C>T		non_coding_transcript_exon_variant	25/25
LRP6	XR_002957325.2	n.8212C>T		non_coding_transcript_exon_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.*4100C>T		3_prime_UTR_variant	23/23	1	NM_002336.3	ENSP00000261349	P1
LRP6	ENST00000538239.5	c.*2379C>T		3_prime_UTR_variant, NMD_transcript_variant	24/24	1		ENSP00000445083
BCL2L14	ENST00000298566.2	c.711+1699G>A		intron_variant, NMD_transcript_variant		2		ENSP00000298566

Frequencies

GnomAD3 genomes AF: 0.0480 AC: 7306 AN: 152068 Hom.: 252 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0470

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.0212

Gnomad FIN AF: 0.0777

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.0634

Gnomad OTH AF: 0.0664

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0480 AC: 7304 AN: 152186 Hom.: 251 Cov.: 32 AF XY: 0.0487 AC XY: 3620 AN XY: 74390

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0469

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.0218

Gnomad4 FIN AF: 0.0777

Gnomad4 NFE AF: 0.0634

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0605 Hom.: 392

Bravo AF: 0.0465

Asia WGS AF: 0.0200 AC: 71 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.62
DANN	Benign	0.68

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: rs3741792; hg19: chr12-12269960;