1-54009040-C-T

Variant names:

• chr1-54009040-C-T
• rs754372945
• NM_001010978.4:c.560G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001010978.4(LDLRAD1):​c.560G>A​(p.Arg187His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: LDLRAD1 NM_001010978.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0950
• Publications: 0 publications found

Genes affected

LDLRAD1 (HGNC:32069): (low density lipoprotein receptor class A domain containing 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36368096).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010978.4. 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
	LDLRAD1	NM_001010978.4	MANE Select	c.560G>A	p.Arg187His	missense	Exon 6 of 6	NP_001010978.2	Q5T700-1
	LDLRAD1	NM_001276392.2		c.443G>A	p.Arg148His	missense	Exon 4 of 4	NP_001263321.1	Q5T700-2
	LDLRAD1	NM_001276393.2		c.431G>A	p.Arg144His	missense	Exon 5 of 5	NP_001263322.1	Q5T700-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAD1	ENST00000371360.2	TSL:1 MANE Select	c.560G>A	p.Arg187His	missense	Exon 6 of 6	ENSP00000360411.1	Q5T700-1
	LDLRAD1	ENST00000420619.5	TSL:1	c.443G>A	p.Arg148His	missense	Exon 4 of 4	ENSP00000411017.1	Q5T700-2
	LDLRAD1	ENST00000545928.5	TSL:1	c.431G>A	p.Arg144His	missense	Exon 5 of 5	ENSP00000445871.1	Q5T700-4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000240 AC: 6 AN: 249776 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000150 AC: 22 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111980

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74288

African (AFR) AF: 0.0000483 AC: 2 AN: 41420

American (AMR) AF: 0.000131 AC: 2 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.095
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.40
Sift	Benign	0.16	T
Sift4G	Benign	0.081	T
Polyphen		0.99	D
Vest4		0.28
MutPred		0.64		Loss of stability (P = 0.0979)
MVP		0.76
MPC		0.28
ClinPred		0.22	T
GERP RS		0.29
Varity_R		0.032
gMVP		0.62
Mutation Taster		=84/16	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: rs754372945; hg19: chr1-54474713;