rs1330017675

Variant names:

• chr1-25543715-C-A
• rs1330017675
• NM_015627.3:c.17C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25543715-C-A
• chr1-25543715-C-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_015627.3(LDLRAP1):​c.17C>A​(p.Ser6*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S6S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDLRAP1 NM_015627.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.08
• Publications: 0 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: Pathogenic. The variant received 13 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-25543715-C-A is Pathogenic according to our data. Variant chr1-25543715-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2697613.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAP1	NM_015627.3	MANE Select	c.17C>A	p.Ser6*	stop_gained	Exon 1 of 9	NP_056442.2	Q5SW96

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAP1	ENST00000374338.5	TSL:1 MANE Select	c.17C>A	p.Ser6*	stop_gained	Exon 1 of 9	ENSP00000363458.4	Q5SW96
	LDLRAP1	ENST00000894925.1		c.17C>A	p.Ser6*	stop_gained	Exon 1 of 10	ENSP00000564984.1
	LDLRAP1	ENST00000894924.1		c.17C>A	p.Ser6*	stop_gained	Exon 1 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151734 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1062600 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 502338

African (AFR) AF: 0.00 AC: 0 AN: 22152

American (AMR) AF: 0.00 AC: 0 AN: 7718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13244

East Asian (EAS) AF: 0.00 AC: 0 AN: 24960

South Asian (SAS) AF: 0.00 AC: 0 AN: 19518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20766

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 908952

Other (OTH) AF: 0.00 AC: 0 AN: 42128

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151734 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74140

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67870

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hypercholesterolemia, familial, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	53
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		2.1
Vest4		0.26
GERP RS		4.0
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1330017675; hg19: chr1-25870206;