19-11132089-A-G

Variant names:

• chr19-11132089-A-G
• rs2738466
• NM_000527.5:c.*773A>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.*773A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 163,236 control chromosomes in the GnomAD database, including 4,438 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4164 hom., cov: 31)
  • Exomes 𝑓: 0.20 (274 hom.)
• Consequence: LDLR NM_000527.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.33
• Publications: 25 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=-0.9).
• BP6: Variant 19-11132089-A-G is Benign according to our data. Variant chr19-11132089-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	NM_000527.5	MANE Select	c.*773A>G		3_prime_UTR	Exon 18 of 18	NP_000518.1
	LDLR	NM_001195798.2		c.*773A>G		3_prime_UTR	Exon 18 of 18	NP_001182727.1
	LDLR	NM_001195799.2		c.*773A>G		3_prime_UTR	Exon 17 of 17	NP_001182728.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLR	ENST00000558518.6	TSL:1 MANE Select	c.*773A>G		3_prime_UTR	Exon 18 of 18	ENSP00000454071.1
	LDLR	ENST00000252444.10	TSL:1	c.*773A>G		3_prime_UTR	Exon 18 of 18	ENSP00000252444.6
	LDLR	ENST00000559340.2	TSL:5	n.*1425A>G		non_coding_transcript_exon	Exon 17 of 17	ENSP00000453696.2

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34671 AN: 152036 Hom.: 4158 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.218

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.202 AC: 2237 AN: 11082 Hom.: 274 Cov.: 0 AF XY: 0.194 AC XY: 1113 AN XY: 5734

African (AFR) AF: 0.100 AC: 5 AN: 50

American (AMR) AF: 0.228 AC: 496 AN: 2176

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 12 AN: 88

East Asian (EAS) AF: 0.274 AC: 58 AN: 212

South Asian (SAS) AF: 0.139 AC: 191 AN: 1376

European-Finnish (FIN) AF: 0.206 AC: 122 AN: 592

Middle Eastern (MID) AF: 0.150 AC: 3 AN: 20

European-Non Finnish (NFE) AF: 0.209 AC: 1277 AN: 6120

Other (OTH) AF: 0.163 AC: 73 AN: 448

GnomAD4 genome AF: 0.228 AC: 34693 AN: 152154 Hom.: 4164 Cov.: 31 AF XY: 0.227 AC XY: 16849 AN XY: 74364

African (AFR) AF: 0.175 AC: 7271 AN: 41514

American (AMR) AF: 0.241 AC: 3679 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 725 AN: 3466

East Asian (EAS) AF: 0.384 AC: 1980 AN: 5160

South Asian (SAS) AF: 0.193 AC: 931 AN: 4822

European-Finnish (FIN) AF: 0.218 AC: 2303 AN: 10586

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.251 AC: 17085 AN: 68020

Other (OTH) AF: 0.230 AC: 485 AN: 2112

Alfa AF: 0.235 Hom.: 5925

Bravo AF: 0.230

Asia WGS AF: 0.297 AC: 1030 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 08, 2019

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Due to the increased occurrence of the mutation (>= 5%) and the current estimates of databases (LOVD 3), this variant is classified as likely benign.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Familial hypercholesterolemia Benign:1

Jun 30, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.092
DANN	Benign	0.37
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2738466; hg19: chr19-11242765; COSMIC: COSV52945342; COSMIC: COSV52945342;