1-21814404-T-A

Position:

• chr1-21814404-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001013693.3(LDLRAD2):​c.92T>A​(p.Leu31Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LDLRAD2 NM_001013693.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.75

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAD2	NM_001013693.3	c.92T>A	p.Leu31Gln	missense_variant	2/5	ENST00000344642.7	NP_001013715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLRAD2	ENST00000344642.7	c.92T>A	p.Leu31Gln	missense_variant	2/5	2	NM_001013693.3	ENSP00000340988.2
LDLRAD2	ENST00000543870.1	c.92T>A	p.Leu31Gln	missense_variant	2/6	1		ENSP00000444097.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000452 AC: 1 AN: 221030 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122320

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

The c.92T>A (p.L31Q) alteration is located in exon 2 (coding exon 2) of the LDLRAD2 gene. This alteration results from a T to A substitution at nucleotide position 92, causing the leucine (L) at amino acid position 31 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.46	.;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.33		Gain of disorder (P = 0.0244);Gain of disorder (P = 0.0244);
MVP		0.62
MPC		0.34
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.44
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs771256125; hg19: chr1-22140897;