19-11100403-C-T

Variant names:

• chr19-11100403-C-T
• rs3745678
• NM_000527.5:c.190+58C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000527.5(LDLR):​c.190+58C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00766 in 1,541,000 control chromosomes in the GnomAD database, including 627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (67 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (560 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.916
• Publications: 4 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-11100403-C-T is Benign according to our data. Variant chr19-11100403-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1712176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000527.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.190+58C>T		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.190+58C>T		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.190+58C>T		intron	N/A	NP_001182728.1	P01130-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.190+58C>T		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.448+58C>T		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.190+58C>T		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1991 AN: 152176 Hom.: 67 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.0115

GnomAD4 exome AF: 0.00707 AC: 9820 AN: 1388706 Hom.: 560 Cov.: 21 AF XY: 0.00686 AC XY: 4760 AN XY: 693824

African (AFR) AF: 0.0221 AC: 708 AN: 32022

American (AMR) AF: 0.0244 AC: 1051 AN: 43086

Ashkenazi Jewish (ASJ) AF: 0.00926 AC: 236 AN: 25494

East Asian (EAS) AF: 0.159 AC: 6203 AN: 39044

South Asian (SAS) AF: 0.00479 AC: 402 AN: 83924

European-Finnish (FIN) AF: 0.00145 AC: 65 AN: 44820

Middle Eastern (MID) AF: 0.00264 AC: 14 AN: 5302

European-Non Finnish (NFE) AF: 0.000572 AC: 605 AN: 1056924

Other (OTH) AF: 0.00923 AC: 536 AN: 58090

GnomAD4 genome AF: 0.0130 AC: 1987 AN: 152294 Hom.: 67 Cov.: 33 AF XY: 0.0142 AC XY: 1054 AN XY: 74474

African (AFR) AF: 0.0194 AC: 806 AN: 41566

American (AMR) AF: 0.0177 AC: 271 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.145 AC: 753 AN: 5176

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4826

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68032

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00487 Hom.: 3

Bravo AF: 0.0153

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.87
DANN	Benign	0.60
PhyloP100		-0.92
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs3745678; hg19: chr19-11211079; COSMIC: COSV52944638; COSMIC: COSV52944638;