rs114583297

chr1-25563697-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015627.3(LDLRAP1):c.653C>T(p.Thr218Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,904 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T218M) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (18 hom.)
• Consequence: LDLRAP1 NM_015627.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:6
• Conservation: PhyloP100: 0.336

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025242567).
• BP6: Variant 1-25563697-C-T is Benign according to our data. Variant chr1-25563697-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520395.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr1-25563697-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00758 (1154/152338) while in subpopulation AFR AF= 0.026 (1079/41574). AF 95% confidence interval is 0.0247. There are 12 homozygotes in gnomad4. There are 490 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAP1	NM_015627.3	c.653C>T	p.Thr218Ile	missense_variant	7/9	ENST00000374338.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.653C>T	p.Thr218Ile	missense_variant	7/9	1	NM_015627.3	P1
LDLRAP1	ENST00000484476.5	n.375C>T		non_coding_transcript_exon_variant	2/4	1
LDLRAP1	ENST00000474283.1	n.64C>T		non_coding_transcript_exon_variant	1/3	3
LDLRAP1	ENST00000488127.1	n.1123C>T		non_coding_transcript_exon_variant	6/7	2

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1147 AN: 152220 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00217 AC: 545 AN: 250890 Hom.: 9 AF XY: 0.00155 AC XY: 211 AN XY: 135692

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000859 AC: 1256 AN: 1461566 Hom.: 18 Cov.: 31 AF XY: 0.000737 AC XY: 536 AN XY: 727086

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00758 AC: 1154 AN: 152338 Hom.: 12 Cov.: 32 AF XY: 0.00658 AC XY: 490 AN XY: 74496

Gnomad4 AFR AF: 0.0260

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00155 Hom.: 1

Bravo AF: 0.00914

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00271 AC: 329

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 4 Pathogenic:1 Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_015627.2:c.653C>T in the LDLRAP1 gene has an allele frequency of 0.028 in African subpopulation in the gnomAD database, including 13 homozygous occurrences. It was detected in one individual with autosomal recessive hypercholesterolemia, compound heterozygous with c.863C>T (p.Ser288Leu) (PMID: 29245109). Benign computational verdict because benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2, BP4, PM3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 08, 2021	- -
Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.08, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Familial hypercholesterolemia Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	8.4
Dann	Benign	0.91
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.034
Sift	Benign	0.40	T
Sift4G	Benign	0.45	T
Polyphen		0.045	B
Vest4		0.13
MVP		0.53
MPC		0.21
ClinPred		0.0044	T
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.072

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: rs114583297; hg19: chr1-25890188;