rs41306974

Variant names:

• chr19-11127961-G-A
• rs41306974
• NM_000527.5:c.2312-47G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11127961-G-A
• chr19-11127961-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000527.5(LDLR):​c.2312-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,549,938 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 31)
  • Exomes 𝑓: 0.013 (151 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.749

Genes affected

LDLR (HGNC:6547): (low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-11127961-G-A is Benign according to our data. Variant chr19-11127961-G-A is described in ClinVar as [Benign]. Clinvar id is 252278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11127961-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1699/152138) while in subpopulation NFE AF = 0.0173 (1173/67986). AF 95% confidence interval is 0.0164. There are 14 homozygotes in GnomAd4. There are 810 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.2312-47G>A		intron_variant	Intron 15 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.2312-47G>A		intron_variant	Intron 15 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1700 AN: 152020 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0104 AC: 2612 AN: 250328 AF XY: 0.0106

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00853

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00714

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0132 AC: 18435 AN: 1397800 Hom.: 151 Cov.: 25 AF XY: 0.0131 AC XY: 9154 AN XY: 699180

Gnomad4 AFR exome AF: 0.00224 AC: 72 AN: 32140

Gnomad4 AMR exome AF: 0.00921 AC: 411 AN: 44646

Gnomad4 ASJ exome AF: 0.0124 AC: 320 AN: 25784

Gnomad4 EAS exome AF: 0.0000508 AC: 2 AN: 39378

Gnomad4 SAS exome AF: 0.00452 AC: 384 AN: 85024

Gnomad4 FIN exome AF: 0.00764 AC: 398 AN: 52098

Gnomad4 NFE exome AF: 0.0153 AC: 16164 AN: 1054932

Gnomad4 Remaining exome AF: 0.0110 AC: 639 AN: 58146

GnomAD4 genome AF: 0.0112 AC: 1699 AN: 152138 Hom.: 14 Cov.: 31 AF XY: 0.0109 AC XY: 810 AN XY: 74362

Gnomad4 AFR AF: 0.00241 AC: 0.00240859 AN: 0.00240859

Gnomad4 AMR AF: 0.0155 AC: 0.0154754 AN: 0.0154754

Gnomad4 ASJ AF: 0.0132 AC: 0.0132488 AN: 0.0132488

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00353 AC: 0.00353137 AN: 0.00353137

Gnomad4 FIN AF: 0.00877 AC: 0.00876862 AN: 0.00876862

Gnomad4 NFE AF: 0.0173 AC: 0.0172536 AN: 0.0172536

Gnomad4 OTH AF: 0.0147 AC: 0.0146641 AN: 0.0146641

Alfa AF: 0.00987 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.1
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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: rs41306974; hg19: chr19-11238637;