4-20257908-G-A

Position:

• chr4-20257908-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP5 BS2

The NM_004787.4(SLIT2):​c.292G>A​(p.Ala98Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,418,734 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: SLIT2 NM_004787.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.92

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-20257908-G-A is Pathogenic according to our data. Variant chr4-20257908-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 684623.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLIT2	NM_004787.4	c.292G>A	p.Ala98Thr	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.292G>A	p.Ala98Thr	missense_variant	3/37	1	NM_004787.4	ENSP00000422591	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1418734 Hom.: 0 Cov.: 23 AF XY: 0.00000141 AC XY: 1 AN XY: 708388

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000372

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital anomaly of kidney and urinary tract Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

May 31, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	.;T;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.53	N;N;.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D;D;.;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.064	T;D;.;D;T;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;T
Polyphen		0.98	D;D;.;.;.;.
Vest4		0.79
MutPred		0.48		Loss of catalytic residue at A98 (P = 0.0317);Loss of catalytic residue at A98 (P = 0.0317);.;Loss of catalytic residue at A98 (P = 0.0317);Loss of catalytic residue at A98 (P = 0.0317);.;
MVP		0.75
MPC		0.74
ClinPred		0.90	D
GERP RS		6.1
Varity_R		0.52
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1577330805; hg19: chr4-20259531;