chr1-54010284-G-A

Position:

• chr1-54010284-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000371360.2(LDLRAD1):​c.467C>T​(p.Pro156Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LDLRAD1 ENST00000371360.2 missense, splice_region
• Scores: Splicing: ADA: 0.9039
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32762122).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAD1	NM_001010978.4	c.467C>T	p.Pro156Leu	missense_variant, splice_region_variant	5/6	ENST00000371360.2	NP_001010978.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LDLRAD1	ENST00000371360.2	c.467C>T	p.Pro156Leu	missense_variant, splice_region_variant	5/6	1	NM_001010978.4	ENSP00000360411	P1
LDLRAD1	ENST00000420619.5	c.350C>T	p.Pro117Leu	missense_variant, splice_region_variant	3/4	1		ENSP00000411017
LDLRAD1	ENST00000545928.5	c.338C>T	p.Pro113Leu	missense_variant, splice_region_variant	4/5	1		ENSP00000445871
LDLRAD1	ENST00000371362.7	c.200C>T	p.Pro67Leu	missense_variant, splice_region_variant	3/4	1		ENSP00000360413

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Apr 08, 2022

The c.467C>T (p.P156L) alteration is located in exon 5 (coding exon 5) of the LDLRAD1 gene. This alteration results from a C to T substitution at nucleotide position 467, causing the proline (P) at amino acid position 156 to be replaced by a leucine (L). 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	Benign	0.11
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Benign	0.97
DEOGEN2	Benign	0.018	.;.;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Benign	0.18
Sift	Benign	0.76	T;T;D;T
Sift4G	Uncertain	0.042	D;T;D;T
Polyphen		0.76	.;.;.;P
Vest4		0.50
MutPred		0.47		.;.;.;Loss of disorder (P = 0.0368);
MVP		0.62
MPC		0.29
ClinPred		0.93	D
GERP RS		4.1
Varity_R		0.11
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-54475957;