19-11131539-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000527.5(LDLR):c.*223G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 700,648 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (6 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.17

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042452216).
• BP6: Variant 19-11131539-G-A is Benign according to our data. Variant chr19-11131539-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 889308.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLR	NM_000527.5	c.*223G>A		3_prime_UTR_variant	18/18	ENST00000558518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLR	ENST00000558518.6	c.*223G>A		3_prime_UTR_variant	18/18	1	NM_000527.5	P3

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00338

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00331 AC: 452 AN: 136726 Hom.: 0 AF XY: 0.00345 AC XY: 256 AN XY: 74158

Gnomad AFR exome AF: 0.000449

Gnomad AMR exome AF: 0.00405

Gnomad ASJ exome AF: 0.00186

Gnomad EAS exome AF: 0.0000921

Gnomad SAS exome AF: 0.00397

Gnomad FIN exome AF: 0.000716

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00321 AC: 1762 AN: 548500 Hom.: 6 Cov.: 3 AF XY: 0.00338 AC XY: 1002 AN XY: 296878

Gnomad4 AFR exome AF: 0.000643

Gnomad4 AMR exome AF: 0.00412

Gnomad4 ASJ exome AF: 0.00156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00387

Gnomad4 FIN exome AF: 0.000646

Gnomad4 NFE exome AF: 0.00372

Gnomad4 OTH exome AF: 0.00345

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74380

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00338

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00247 Hom.: 0

Bravo AF: 0.00206

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ExAC AF: 0.00176 AC: 97

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.014
Dann	Benign	0.50
DEOGEN2	Benign	0.0090	T
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0042	T
MutationTaster	Benign	1.0	N;N;N;N
MVP		0.21
GERP RS		-6.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs17243011; hg19: chr19-11242215;