4-61813881-C-G

Position:

• chr4-61813881-C-G

Variant summary

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

The NM_001387552.1(ADGRL3):​c.1472C>G​(p.Ser491Cys) 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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRL3 NM_001387552.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

Genes affected

ADGRL3 (HGNC:20974): (adhesion G protein-coupled receptor L3) This gene encodes a member of the latrophilin subfamily of G-protein coupled receptors (GPCR). Latrophilins may function in both cell adhesion and signal transduction. In experiments with non-human species, endogenous proteolytic cleavage within a cysteine-rich GPS (G-protein-coupled-receptor proteolysis site) domain resulted in two subunits (a large extracellular N-terminal cell adhesion subunit and a subunit with substantial similarity to the secretin/calcitonin family of GPCRs) being non-covalently bound at the cell membrane. [provided by RefSeq, Jul 2008]

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=0.07185227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRL3	NM_001387552.1	c.1472C>G	p.Ser491Cys	missense_variant	9/27	ENST00000683033.1	NP_001374481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRL3	ENST00000683033.1	c.1472C>G	p.Ser491Cys	missense_variant	9/27		NM_001387552.1	ENSP00000507980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

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

May 26, 2024

The c.1268C>G (p.S423C) alteration is located in exon 6 (coding exon 6) of the ADGRL3 gene. This alteration results from a C to G substitution at nucleotide position 1268, causing the serine (S) at amino acid position 423 to be replaced by a cysteine (C). 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
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.020	.;.;.;T;T;T;.;T;.;T;T;T;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.072	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.12	B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.18
MutPred		0.27		Loss of phosphorylation at S423 (P = 0.0149);Loss of phosphorylation at S423 (P = 0.0149);.;.;Loss of phosphorylation at S423 (P = 0.0149);.;.;.;Loss of phosphorylation at S423 (P = 0.0149);Loss of phosphorylation at S423 (P = 0.0149);Loss of phosphorylation at S423 (P = 0.0149);.;.;Loss of phosphorylation at S423 (P = 0.0149);
MVP		0.068
MPC		0.35
ClinPred		0.12	T
GERP RS		1.9
gMVP		0.50

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-62679599;