rs6687605

Variant names:

• chr1-25563141-T-C
• rs6687605
• NM_015627.3:c.604T>C

Your query was ambiguous. Multiple possible variants found:

• chr1-25563141-T-C
• chr1-25563141-T-G
• chr1-25563141-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015627.3(LDLRAP1):​c.604T>C​(p.Ser202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,611,136 control chromosomes in the GnomAD database, including 218,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S202H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.48 (17958 hom., cov: 31)
  • Exomes 𝑓: 0.52 (200701 hom.)
• Consequence: LDLRAP1 NM_015627.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.666
• Publications: 51 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5136673E-5).
• BP6: Variant 1-25563141-T-C is Benign according to our data. Variant chr1-25563141-T-C is described in ClinVar as Benign. ClinVar VariationId is 296982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

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.604T>C	p.Ser202Pro	missense	Exon 6 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.604T>C	p.Ser202Pro	missense	Exon 6 of 9	ENSP00000363458.4	Q5SW96
	LDLRAP1	ENST00000484476.5	TSL:1	n.326T>C		non_coding_transcript_exon	Exon 1 of 4
	LDLRAP1	ENST00000894925.1		c.667T>C	p.Ser223Pro	missense	Exon 7 of 10	ENSP00000564984.1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72733 AN: 151808 Hom.: 17949 Cov.: 31

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.525

GnomAD2 exomes AF: 0.505 AC: 126613 AN: 250530 AF XY: 0.506

Gnomad AFR exome AF: 0.351

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.581

Gnomad EAS exome AF: 0.448

Gnomad FIN exome AF: 0.504

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.537

GnomAD4 exome AF: 0.522 AC: 762025 AN: 1459208 Hom.: 200701 Cov.: 39 AF XY: 0.521 AC XY: 378270 AN XY: 726082

African (AFR) AF: 0.355 AC: 11858 AN: 33432

American (AMR) AF: 0.547 AC: 24449 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.587 AC: 15329 AN: 26100

East Asian (EAS) AF: 0.500 AC: 19827 AN: 39670

South Asian (SAS) AF: 0.435 AC: 37478 AN: 86192

European-Finnish (FIN) AF: 0.496 AC: 26476 AN: 53372

Middle Eastern (MID) AF: 0.566 AC: 3259 AN: 5756

European-Non Finnish (NFE) AF: 0.534 AC: 592471 AN: 1109680

Other (OTH) AF: 0.512 AC: 30878 AN: 60296

GnomAD4 genome AF: 0.479 AC: 72780 AN: 151928 Hom.: 17958 Cov.: 31 AF XY: 0.476 AC XY: 35369 AN XY: 74248

African (AFR) AF: 0.354 AC: 14675 AN: 41436

American (AMR) AF: 0.521 AC: 7948 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2034 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2454 AN: 5166

South Asian (SAS) AF: 0.446 AC: 2144 AN: 4808

European-Finnish (FIN) AF: 0.500 AC: 5278 AN: 10556

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.538 AC: 36532 AN: 67912

Other (OTH) AF: 0.523 AC: 1104 AN: 2110

Alfa AF: 0.516 Hom.: 76770

Bravo AF: 0.477

TwinsUK AF: 0.546 AC: 2025

ALSPAC AF: 0.539 AC: 2078

ESP6500AA AF: 0.345 AC: 1519

ESP6500EA AF: 0.533 AC: 4583

ExAC AF: 0.499 AC: 60644

Asia WGS AF: 0.427 AC: 1485 AN: 3478

EpiCase AF: 0.546

EpiControl AF: 0.537

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Hypercholesterolemia, familial, 4 (5)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Familial hypercholesterolemia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.9
DANN	Benign	0.60
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.000025	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.67
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.041
Sift	Benign	0.14	T
Sift4G	Benign	0.16	T
Polyphen		0.079	B
Vest4		0.069
MPC		0.25
ClinPred		0.0090	T
GERP RS		-2.4
Varity_R		0.073
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6687605; hg19: chr1-25889632; COSMIC: COSV65473260; COSMIC: COSV65473260;