Genetic Variant LDLRAD2:p.Arg47Leu (chr1-21814452-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001013693.3(LDLRAD2):c.140G>T(p.Arg47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,610,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

LDLRAD2
NM_001013693.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.32

Publications

2 publications found

Variant links:

Genes affected

LDLRAD2 (HGNC:32071): (low density lipoprotein receptor class A domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

LDLRAD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19595283).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013693.3. 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
	LDLRAD2	NM_001013693.3	MANE Select	c.140G>T	p.Arg47Leu	missense	Exon 2 of 5	NP_001013715.2	Q5SZI1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAD2	ENST00000344642.7	TSL:2 MANE Select	c.140G>T	p.Arg47Leu	missense	Exon 2 of 5	ENSP00000340988.2	Q5SZI1
	LDLRAD2	ENST00000543870.1	TSL:1	c.140G>T	p.Arg47Leu	missense	Exon 2 of 6	ENSP00000444097.1	Q5SZI1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000425

AC:

AN:

235430

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000977

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000686

AC:

AN:

1458284

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725220

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.00

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26032

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1110716

Other (OTH)

AF:

0.00

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.050

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.46

M_CAP

Uncertain

0.088

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

1.3

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.082

Sift

Benign

0.087

Sift4G

Uncertain

0.023

Polyphen

0.65

Vest4

0.12

MutPred

0.45

Loss of catalytic residue at R47 (P = 0.0571)

MVP

0.45

MPC

0.54

ClinPred

0.44

GERP RS

2.1

Varity_R

0.18

gMVP

0.58

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over