NM_015627.3:c.18G>A

Variant names:

• chr1-25543716-G-A
• NM_015627.3:c.18G>A

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.18G>A​(p.Ser6Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000941 in 1,062,620 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. S6S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: LDLRAP1 NM_015627.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.38
• 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=-0.45).
• BP6: Variant 1-25543716-G-A is Benign according to our data. Variant chr1-25543716-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2046076.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 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.18G>A	p.Ser6Ser	synonymous	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.18G>A	p.Ser6Ser	synonymous	Exon 1 of 9	ENSP00000363458.4	Q5SW96
	LDLRAP1	ENST00000894925.1		c.18G>A	p.Ser6Ser	synonymous	Exon 1 of 10	ENSP00000564984.1
	LDLRAP1	ENST00000894924.1		c.18G>A	p.Ser6Ser	synonymous	Exon 1 of 10	ENSP00000564983.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.41e-7 AC: 1 AN: 1062620 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: 7722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13242

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

South Asian (SAS) AF: 0.0000512 AC: 1 AN: 19514

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3150

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 908976

Other (OTH) AF: 0.00 AC: 0 AN: 42138

GnomAD4 genome Cov.: 32

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	-0.45
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		-1.4
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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

hg19: chr1-25870207;