1-25568362-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015627.3(LDLRAP1):c.*1370G>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 0.528 in 152,208 control chromosomes in the GnomAD database, including 21,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.53 (21977 hom., cov: 32)
  • Exomes 𝑓: 0.45 (8 hom.)
• Consequence: LDLRAP1 NM_015627.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.438

Genes affected

LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-25568362-G-T is Benign according to our data. Variant chr1-25568362-G-T is described in ClinVar as [Benign]. Clinvar id is 297011.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAP1	NM_015627.3	c.*1370G>T		3_prime_UTR_variant	9/9	ENST00000374338.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.*1370G>T		3_prime_UTR_variant	9/9	1	NM_015627.3	P1
LDLRAP1	ENST00000488127.1	n.4148G>T		non_coding_transcript_exon_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.528 AC: 80231 AN: 151972 Hom.: 21947 Cov.: 32

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.523

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.484

GnomAD4 exome AF: 0.449 AC: 53 AN: 118 Hom.: 8 Cov.: 0 AF XY: 0.417 AC XY: 25 AN XY: 60

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.453

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.528 AC: 80317 AN: 152090 Hom.: 21977 Cov.: 32 AF XY: 0.530 AC XY: 39433 AN XY: 74334

Gnomad4 AFR AF: 0.680

Gnomad4 AMR AF: 0.476

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.522

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.458

Gnomad4 OTH AF: 0.486

Alfa AF: 0.460 Hom.: 16093

Bravo AF: 0.531

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.3
Dann	Benign	0.81

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: rs11563; hg19: chr1-25894853;