1-25568362-G-T

Variant names:

• chr1-25568362-G-T
• rs11563
• NM_015627.3:c.*1370G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.438
• Publications: 19 publications found

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]

LDLRAP1 Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 297011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015627.3. 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
	LDLRAP1	NM_015627.3	MANE Select	c.*1370G>T		3_prime_UTR	Exon 9 of 9	NP_056442.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAP1	ENST00000374338.5	TSL:1 MANE Select	c.*1370G>T		3_prime_UTR	Exon 9 of 9	ENSP00000363458.4
	LDLRAP1	ENST00000488127.1	TSL:2	n.4148G>T		non_coding_transcript_exon	Exon 7 of 7
	LDLRAP1	ENST00000718277.1		c.782+3155G>T		intron	N/A	ENSP00000520715.1

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

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.453 AC: 39 AN: 86

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 10 AN: 20

Other (OTH) AF: 0.375 AC: 3 AN: 8

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

African (AFR) AF: 0.680 AC: 28218 AN: 41484

American (AMR) AF: 0.476 AC: 7280 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1417 AN: 3470

East Asian (EAS) AF: 0.522 AC: 2695 AN: 5158

South Asian (SAS) AF: 0.550 AC: 2653 AN: 4828

European-Finnish (FIN) AF: 0.500 AC: 5283 AN: 10562

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31153 AN: 67990

Other (OTH) AF: 0.486 AC: 1026 AN: 2112

Alfa AF: 0.472 Hom.: 22132

Bravo AF: 0.531

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hypercholesterolemia, familial, 4 Benign:1

Jan 12, 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.3
DANN	Benign	0.81
PhyloP100		-0.44
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: rs11563; hg19: chr1-25894853;