rs34113544

Variant names:

• chr19-11132531-C-CA
• rs34113544
• NM_000527.5:c.*1216dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000527.5(LDLR):​c.*1216dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (21431 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.927

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 -10 ACMG points.

• BP6: Variant 19-11132531-C-CA is Benign according to our data. Variant chr19-11132531-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 328087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.695 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLR	NM_000527.5	c.*1216dupA		3_prime_UTR_variant	Exon 18 of 18	ENST00000558518.6	NP_000518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLR	ENST00000558518.6	c.*1216dupA		3_prime_UTR_variant	Exon 18 of 18	1	NM_000527.5	ENSP00000454071.1

Frequencies

GnomAD3 genomes AF: 0.571 AC: 67896 AN: 118824 Hom.: 21434 Cov.: 0

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.652

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.562

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 AFR exome AC: 0 AN: 0

Gnomad4 AMR exome AC: 0 AN: 0

Gnomad4 ASJ exome AC: 0 AN: 0

Gnomad4 EAS exome AC: 0 AN: 0

Gnomad4 SAS exome AC: 0 AN: 0

Gnomad4 FIN exome AC: 0 AN: 0

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 2

Gnomad4 Remaining exome AC: 0 AN: 0

GnomAD4 genome AF: 0.571 AC: 67912 AN: 118920 Hom.: 21431 Cov.: 0 AF XY: 0.563 AC XY: 31608 AN XY: 56182

Gnomad4 AFR AF: 0.320 AC: 0.320173 AN: 0.320173

Gnomad4 AMR AF: 0.640 AC: 0.639513 AN: 0.639513

Gnomad4 ASJ AF: 0.652 AC: 0.651916 AN: 0.651916

Gnomad4 EAS AF: 0.622 AC: 0.621976 AN: 0.621976

Gnomad4 SAS AF: 0.579 AC: 0.578775 AN: 0.578775

Gnomad4 FIN AF: 0.668 AC: 0.668115 AN: 0.668115

Gnomad4 NFE AF: 0.700 AC: 0.700481 AN: 0.700481

Gnomad4 OTH AF: 0.559 AC: 0.558518 AN: 0.558518

Alfa AF: 0.628 Hom.: 3424

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs34113544; hg19: chr19-11243207; COSMIC: COSV52946100;