rs2738467

Variant names:

• chr19-11133059-C-T
• rs2738467
• NM_000527.5:c.*1743C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-11133059-C-T
• chr19-11133059-C-G

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.*1743C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 151,446 control chromosomes in the GnomAD database, including 10,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (10219 hom., cov: 30)
  • Exomes 𝑓: 0.54 (4 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.84
• Publications: 17 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]

SPC24 (HGNC:26913): (SPC24 component of NDC80 kinetochore complex) Predicted to be involved in cell division. Located in nucleolus and nucleoplasm. Part of Ndc80 complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-11133059-C-T is Benign according to our data. Variant chr19-11133059-C-T is described in ClinVar as Benign. ClinVar VariationId is 328106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 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.*1743C>T		3_prime_UTR	Exon 18 of 18	NP_000518.1	P01130-1
	LDLR	NM_001195798.2		c.*1743C>T		3_prime_UTR	Exon 18 of 18	NP_001182727.1	P01130-5
	LDLR	NM_001195799.2		c.*1743C>T		3_prime_UTR	Exon 17 of 17	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.*1743C>T		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1	P01130-1
	LDLR	ENST00000252444.10	TSL:1	c.*1743C>T		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6	J3KMZ9
	LDLR	ENST00000913405.1		c.*1743C>T		3_prime_UTR	Exon 18 of 18	ENSP00000583464.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50200 AN: 151302 Hom.: 10228 Cov.: 30

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.374

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.426

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.368

GnomAD4 exome AF: 0.542 AC: 13 AN: 24 Hom.: 4 Cov.: 0 AF XY: 0.438 AC XY: 7 AN XY: 16

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.611 AC: 11 AN: 18

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.331 AC: 50187 AN: 151422 Hom.: 10219 Cov.: 30 AF XY: 0.336 AC XY: 24834 AN XY: 73938

African (AFR) AF: 0.0875 AC: 3613 AN: 41286

American (AMR) AF: 0.426 AC: 6460 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1332 AN: 3464

East Asian (EAS) AF: 0.191 AC: 975 AN: 5118

South Asian (SAS) AF: 0.374 AC: 1796 AN: 4802

European-Finnish (FIN) AF: 0.499 AC: 5216 AN: 10454

Middle Eastern (MID) AF: 0.414 AC: 120 AN: 290

European-Non Finnish (NFE) AF: 0.437 AC: 29625 AN: 67840

Other (OTH) AF: 0.367 AC: 770 AN: 2100

Alfa AF: 0.338 Hom.: 3211

Bravo AF: 0.314

Asia WGS AF: 0.258 AC: 896 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypercholesterolemia, familial, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.099
DANN	Benign	0.47
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2738467; hg19: chr19-11243735;