rs3745677

Variant names:

• chr19-11100401-G-A
• rs3745677
• NM_000527.5:c.190+56G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-11100401-G-A
• chr19-11100401-G-C
• chr19-11100401-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000527.5(LDLR):​c.190+56G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 1,540,584 control chromosomes in the GnomAD database, including 3,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (851 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3089 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.720
• Publications: 10 publications found

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]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-11100401-G-A is Benign according to our data. Variant chr19-11100401-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 251053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.190+56G>A		intron_variant	Intron 2 of 17	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.190+56G>A		intron_variant	Intron 2 of 17	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.0926 AC: 14073 AN: 151898 Hom.: 853 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0595

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.0258

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.0845

GnomAD4 exome AF: 0.0640 AC: 88813 AN: 1388568 Hom.: 3089 Cov.: 22 AF XY: 0.0627 AC XY: 43510 AN XY: 693534

African (AFR) AF: 0.174 AC: 5590 AN: 32158

American (AMR) AF: 0.0546 AC: 2341 AN: 42880

Ashkenazi Jewish (ASJ) AF: 0.0514 AC: 1308 AN: 25444

East Asian (EAS) AF: 0.0806 AC: 3146 AN: 39010

South Asian (SAS) AF: 0.0249 AC: 2088 AN: 83840

European-Finnish (FIN) AF: 0.0751 AC: 3364 AN: 44772

Middle Eastern (MID) AF: 0.0450 AC: 238 AN: 5288

European-Non Finnish (NFE) AF: 0.0633 AC: 66914 AN: 1057170

Other (OTH) AF: 0.0659 AC: 3824 AN: 58006

GnomAD4 genome AF: 0.0926 AC: 14083 AN: 152016 Hom.: 851 Cov.: 32 AF XY: 0.0897 AC XY: 6668 AN XY: 74318

African (AFR) AF: 0.172 AC: 7141 AN: 41474

American (AMR) AF: 0.0594 AC: 906 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 166 AN: 3472

East Asian (EAS) AF: 0.0607 AC: 313 AN: 5158

South Asian (SAS) AF: 0.0258 AC: 124 AN: 4808

European-Finnish (FIN) AF: 0.0741 AC: 785 AN: 10592

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0652 AC: 4430 AN: 67946

Other (OTH) AF: 0.0826 AC: 174 AN: 2106

Alfa AF: 0.0329 Hom.: 20

Bravo AF: 0.0958

Asia WGS AF: 0.0450 AC: 157 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:3

Mar 25, 2016

LDLR-LOVD, British Heart Foundation

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

-

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	-0.90
CADD	Benign	0.40
DANN	Benign	0.53
PhyloP100		-0.72
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: rs3745677; hg19: chr19-11211077; COSMIC: COSV52942256; COSMIC: COSV52942256;