chr18-13645436-A-T

Position:

• chr18-13645436-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378100.1(LDLRAD4):​c.700A>T​(p.Asn234Tyr) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LDLRAD4 NM_001378100.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

Genes affected

LDLRAD4 (HGNC:1224): (low density lipoprotein receptor class A domain containing 4) Enables R-SMAD binding activity. Involved in negative regulation of cell migration; negative regulation of epithelial to mesenchymal transition; and negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway. Located in early endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20448816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LDLRAD4	NM_001378100.1	c.700A>T	p.Asn234Tyr	missense_variant	7/7	ENST00000359446.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LDLRAD4	ENST00000359446.11	c.700A>T	p.Asn234Tyr	missense_variant	7/7	1	NM_001378100.1	P1
	ENST00000588397.1	n.155+95T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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 05, 2023

The c.700A>T (p.N234Y) alteration is located in exon 7 (coding exon 5) of the LDLRAD4 gene. This alteration results from a A to T substitution at nucleotide position 700, causing the asparagine (N) at amino acid position 234 to be replaced by a tyrosine (Y). 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	0.23
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	0.14
Eigen_PC	Benign	0.071
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		0.80	P;P;.;.;.;.
Vest4		0.38
MutPred		0.29		.;Loss of solvent accessibility (P = 0.0174);.;.;.;.;
MVP		0.41
ClinPred		0.97	D
GERP RS		-0.34
Varity_R		0.38
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-13645435;