1-25543619-C-A

Variant names:

• chr1-25543619-C-A
• rs575024313
• NM_015627.3:c.-80C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015627.3(LDLRAP1):​c.-80C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,024,358 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: LDLRAP1 NM_015627.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.287
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 1-25543619-C-A is Benign according to our data. Variant chr1-25543619-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 875152.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00147 (224/151944) while in subpopulation AFR AF = 0.00532 (221/41514). AF 95% confidence interval is 0.00475. There are 1 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.-80C>A		5_prime_UTR	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.-80C>A		5_prime_UTR	Exon 1 of 9	ENSP00000363458.4	Q5SW96
	LDLRAP1	ENST00000894925.1		c.-80C>A		5_prime_UTR	Exon 1 of 10	ENSP00000564984.1
	LDLRAP1	ENST00000894924.1		c.-80C>A		5_prime_UTR	Exon 1 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 151838 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000479

GnomAD4 exome AF: 0.000130 AC: 113 AN: 872414 Hom.: 0 Cov.: 12 AF XY: 0.000128 AC XY: 53 AN XY: 415166

African (AFR) AF: 0.00567 AC: 103 AN: 18150

American (AMR) AF: 0.00 AC: 0 AN: 6852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11306

East Asian (EAS) AF: 0.00 AC: 0 AN: 22346

South Asian (SAS) AF: 0.0000630 AC: 1 AN: 15870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2454

European-Non Finnish (NFE) AF: 0.00000270 AC: 2 AN: 740352

Other (OTH) AF: 0.000199 AC: 7 AN: 35240

GnomAD4 genome AF: 0.00147 AC: 224 AN: 151944 Hom.: 1 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74286

African (AFR) AF: 0.00532 AC: 221 AN: 41514

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67914

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00148

Asia WGS AF: 0.000596 AC: 2 AN: 3368

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hypercholesterolemia, familial, 4 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.29
PromoterAI		0.0011	Neutral
Mutation Taster		=300/0	polymorphism

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: rs575024313; hg19: chr1-25870110;