chr19-11110797-T-G

Variant names:

• chr19-11110797-T-G
• rs375850141
• NM_000527.5:c.1060+26T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000527.5(LDLR):​c.1060+26T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,610,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: LDLR NM_000527.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.09
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-11110797-T-G is Benign according to our data. Variant chr19-11110797-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 251628.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1060+26T>G		intron	N/A	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.1060+26T>G		intron	N/A	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.937+26T>G		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.1060+26T>G		intron	N/A	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.1318+26T>G		intron	N/A	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000558013.5	TSL:1	c.1060+26T>G		intron	N/A	ENSP00000453346.1	P01130-5

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000301 AC: 75 AN: 248886 AF XY: 0.000415

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1458688 Hom.: 0 Cov.: 34 AF XY: 0.000223 AC XY: 162 AN XY: 725794

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.0000671 AC: 3 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00237 AC: 204 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50854

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111548

Other (OTH) AF: 0.000116 AC: 7 AN: 60342

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.068
DANN	Benign	0.69
PhyloP100		-2.1
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: rs375850141; hg19: chr19-11221473;