rs148916767

Variant names:

• chr1-25557259-C-A
• rs148916767
• NM_015627.3:c.451C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-25557259-C-A
• chr1-25557259-C-T
• chr1-25557259-C-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_015627.3(LDLRAP1):​c.451C>A​(p.Arg151Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,597,656 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: LDLRAP1 NM_015627.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.71
• Publications: 7 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 1-25557259-C-A is Benign according to our data. Variant chr1-25557259-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1552959.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.71 with no splicing effect.

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.451C>A	p.Arg151Arg	synonymous	Exon 4 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.451C>A	p.Arg151Arg	synonymous	Exon 4 of 9	ENSP00000363458.4	Q5SW96
	LDLRAP1	ENST00000894925.1		c.514C>A	p.Arg172Arg	synonymous	Exon 5 of 10	ENSP00000564984.1
	LDLRAP1	ENST00000894924.1		c.451C>A	p.Arg151Arg	synonymous	Exon 4 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151708 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 AF: 0.00000277 AC: 4 AN: 1445948 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719870

African (AFR) AF: 0.00 AC: 0 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 44502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25804

East Asian (EAS) AF: 0.00 AC: 0 AN: 39232

South Asian (SAS) AF: 0.00 AC: 0 AN: 85982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1099282

Other (OTH) AF: 0.00 AC: 0 AN: 59726

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151708 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74108

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

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	-0.24
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148916767; hg19: chr1-25883750;