1-25543719-G-T

Variant names:

• chr1-25543719-G-T
• rs1397505429
• NM_015627.3:c.21G>T

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.21G>T​(p.Ala7Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,752 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 (★). Synonymous variant affecting the same amino acid position (i.e. A7A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LDLRAP1 NM_015627.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.507
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-25543719-G-T is Benign according to our data. Variant chr1-25543719-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1596150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.507 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LDLRAP1	NM_015627.3	c.21G>T	p.Ala7Ala	synonymous_variant	Exon 1 of 9	ENST00000374338.5	NP_056442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LDLRAP1	ENST00000374338.5	c.21G>T	p.Ala7Ala	synonymous_variant	Exon 1 of 9	1	NM_015627.3	ENSP00000363458.4
LDLRAP1	ENST00000718277.1	c.21G>T	p.Ala7Ala	synonymous_variant	Exon 1 of 10			ENSP00000520715.1
LDLRAP1	ENST00000718287.1	c.21G>T	p.Ala7Ala	synonymous_variant	Exon 1 of 6			ENSP00000520725.1
LDLRAP1	ENST00000718288.1	n.21G>T		non_coding_transcript_exon_variant	Exon 1 of 10			ENSP00000520726.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151752 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: 0.00318

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: 1062752 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 502414

African (AFR) AF: 0.00 AC: 0 AN: 22160

American (AMR) AF: 0.00 AC: 0 AN: 7728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13248

East Asian (EAS) AF: 0.00 AC: 0 AN: 24978

South Asian (SAS) AF: 0.00 AC: 0 AN: 19508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3154

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 909058

Other (OTH) AF: 0.00 AC: 0 AN: 42146

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151752 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74136

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15224

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00318 AC: 1 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67892

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, familial, 4 Benign:1

Sep 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.8
DANN	Benign	0.96
PhyloP100		-0.51
PromoterAI		0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=99/1	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: rs1397505429; hg19: chr1-25870210;