rs2738447

Variant names:

• chr19-11116804-A-C
• rs2738447
• NM_000527.5:c.1706-55A>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.1706-55A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 1,602,688 control chromosomes in the GnomAD database, including 295,859 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32604 hom., cov: 33)
  • Exomes 𝑓: 0.60 (263255 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.581

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-11116804-A-C is Benign according to our data. Variant chr19-11116804-A-C is described in ClinVar as [Benign]. Clinvar id is 440657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11116804-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.1706-55A>C		intron_variant	Intron 11 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.1706-55A>C		intron_variant	Intron 11 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98578 AN: 151922 Hom.: 32551 Cov.: 33

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.682

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.628

GnomAD4 exome AF: 0.601 AC: 871857 AN: 1450648 Hom.: 263255 AF XY: 0.600 AC XY: 433462 AN XY: 722208

Gnomad4 AFR exome AF: 0.784

Gnomad4 AMR exome AF: 0.700

Gnomad4 ASJ exome AF: 0.594

Gnomad4 EAS exome AF: 0.612

Gnomad4 SAS exome AF: 0.616

Gnomad4 FIN exome AF: 0.609

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.605

GnomAD4 genome AF: 0.649 AC: 98682 AN: 152040 Hom.: 32604 Cov.: 33 AF XY: 0.650 AC XY: 48313 AN XY: 74292

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.614

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.626

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.626

Alfa AF: 0.615 Hom.: 3637

Bravo AF: 0.658

Asia WGS AF: 0.584 AC: 2035 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided Benign:1

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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	-0.91
CADD	Benign	1.2
DANN	Benign	0.54

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: rs2738447; hg19: chr19-11227480;