rs887610609

Variant names:

• chr1-25543624-G-T
• rs887610609
• NM_015627.3:c.-75G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015627.3(LDLRAP1):​c.-75G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,062,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: LDLRAP1 NM_015627.3 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.721
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000461 (7/151838) while in subpopulation EAS AF = 0.00135 (7/5172). AF 95% confidence interval is 0.000634. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-75G>T		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.-75G>T		5_prime_UTR	Exon 1 of 9	ENSP00000363458.4	Q5SW96
	LDLRAP1	ENST00000894925.1		c.-75G>T		5_prime_UTR	Exon 1 of 10	ENSP00000564984.1
	LDLRAP1	ENST00000894924.1		c.-75G>T		5_prime_UTR	Exon 1 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151838 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: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 4 AN: 910908 Hom.: 0 Cov.: 13 AF XY: 0.00000231 AC XY: 1 AN XY: 432898

African (AFR) AF: 0.00 AC: 0 AN: 18854

American (AMR) AF: 0.00 AC: 0 AN: 6966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11584

East Asian (EAS) AF: 0.000132 AC: 3 AN: 22718

South Asian (SAS) AF: 0.00 AC: 0 AN: 16706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2540

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 775060

Other (OTH) AF: 0.0000274 AC: 1 AN: 36514

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151838 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74184

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

American (AMR) AF: 0.00 AC: 0 AN: 15242

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

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10500

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67904

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

ClinVar submissions

Significance: Uncertain significance

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_noAF	Benign	-0.69
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		0.72
PromoterAI		-0.17	Neutral
Mutation Taster		=297/3	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: rs887610609; hg19: chr1-25870115;