4-20257876-T-G

Position:

• chr4-20257876-T-G

Variant summary

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

The NM_004787.4(SLIT2):​c.260T>G​(p.Met87Arg) 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: SLIT2 NM_004787.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14

Genes affected

SLIT2 (HGNC:11086): (slit guidance ligand 2) This gene encodes a member of the slit family of secreted glycoproteins, which are ligands for the Robo family of immunoglobulin receptors. Slit proteins play highly conserved roles in axon guidance and neuronal migration and may also have functions during other cell migration processes including leukocyte migration. Members of the slit family are characterized by an N-terminal signal peptide, four leucine-rich repeats, nine epidermal growth factor repeats, and a C-terminal cysteine knot. Proteolytic processing of this protein gives rise to an N-terminal fragment that contains the four leucine-rich repeats and five epidermal growth factor repeats and a C-terminal fragment that contains four epidermal growth factor repeats and the cysteine knot. Both full length and cleaved proteins are secreted extracellularly and can function in axon repulsion as well as other specific processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2015]

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
SLIT2	NM_004787.4	c.260T>G	p.Met87Arg	missense_variant	3/37	ENST00000504154.6	NP_004778.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLIT2	ENST00000504154.6	c.260T>G	p.Met87Arg	missense_variant	3/37	1	NM_004787.4	ENSP00000422591.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLIT2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2023

The SLIT2 c.260T>G variant is predicted to result in the amino acid substitution p.Met87Arg. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	.;T;.;.;.;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-1.8	N;N;.;.;N;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;N;.;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.062	T;T;.;T;T;T
Sift4G	Benign	0.20	T;T;D;T;T;T
Polyphen		0.70	P;P;.;.;.;.
Vest4		0.90
MutPred		0.51		Loss of catalytic residue at M87 (P = 0.0148);Loss of catalytic residue at M87 (P = 0.0148);.;Loss of catalytic residue at M87 (P = 0.0148);Loss of catalytic residue at M87 (P = 0.0148);.;
MVP		0.63
MPC		1.3
ClinPred		0.93	D
GERP RS		6.1
Varity_R		0.52
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.37		Position offset: -8

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: chr4-20259499;