NM_174902.4:c.532G>A

Variant names:

• chr11-36227162-G-A
• rs765269452
• NM_174902.4:c.532G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_174902.4(LDLRAD3):​c.532G>A​(p.Gly178Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: LDLRAD3 NM_174902.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14
• Publications: 1 publications found

Genes affected

LDLRAD3 (HGNC:27046): (low density lipoprotein receptor class A domain containing 3) Predicted to enable amyloid-beta binding activity. Predicted to act upstream of or within receptor-mediated endocytosis and regulation of protein processing. Predicted to be located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.758

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174902.4. 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
	LDLRAD3	NM_174902.4	MANE Select	c.532G>A	p.Gly178Ser	missense	Exon 5 of 6	NP_777562.1	Q86YD5-1
	LDLRAD3	NM_001304263.2		c.385G>A	p.Gly129Ser	missense	Exon 4 of 5	NP_001291192.1	Q86YD5-2
	LDLRAD3	NM_001304264.2		c.169G>A	p.Gly57Ser	missense	Exon 5 of 6	NP_001291193.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LDLRAD3	ENST00000315571.6	TSL:1 MANE Select	c.532G>A	p.Gly178Ser	missense	Exon 5 of 6	ENSP00000318607.5	Q86YD5-1
	LDLRAD3	ENST00000528989.5	TSL:1	c.385G>A	p.Gly129Ser	missense	Exon 4 of 5	ENSP00000433954.1	Q86YD5-2
	LDLRAD3	ENST00000872891.1		c.529G>A	p.Gly177Ser	missense	Exon 5 of 6	ENSP00000542950.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251278 AF XY: 0.0000663

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000895 AC: 4 AN: 44708

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111960

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000119

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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.60		Gain of sheet (P = 0.0043)
MVP		0.89
MPC		0.74
ClinPred		0.35	T
GERP RS		5.1
Varity_R		0.38
gMVP		0.83
Mutation Taster		=50/50

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: rs765269452; hg19: chr11-36248712; COSMIC: COSV59688180;