NM_004787.4:c.219A>G

Variant names:

• chr4-20256711-A-G
• rs1476281863
• NM_004787.4:c.219A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_004787.4(SLIT2):​c.219A>G​(p.Thr73Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000254 in 1,576,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLIT2 NM_004787.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0150
• Publications: 0 publications found

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]

SLIT2 Gene-Disease associations (from GenCC):

• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-20256711-A-G is Benign according to our data. Variant chr4-20256711-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3350479.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.015 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004787.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT2	NM_004787.4	MANE Select	c.219A>G	p.Thr73Thr	synonymous	Exon 2 of 37	NP_004778.1	O94813-1
	SLIT2	NM_001289135.3		c.219A>G	p.Thr73Thr	synonymous	Exon 2 of 37	NP_001276064.1	O94813-2
	SLIT2	NM_001289136.3		c.219A>G	p.Thr73Thr	synonymous	Exon 2 of 36	NP_001276065.1	O94813-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT2	ENST00000504154.6	TSL:1 MANE Select	c.219A>G	p.Thr73Thr	synonymous	Exon 2 of 37	ENSP00000422591.1	O94813-1
	SLIT2	ENST00000503837.5	TSL:1	c.219A>G	p.Thr73Thr	synonymous	Exon 2 of 37	ENSP00000422261.1	O94813-2
	SLIT2	ENST00000503823.5	TSL:1	c.219A>G	p.Thr73Thr	synonymous	Exon 2 of 36	ENSP00000427548.1	O94813-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424522 Hom.: 0 Cov.: 24 AF XY: 0.00000282 AC XY: 2 AN XY: 709832

African (AFR) AF: 0.0000618 AC: 2 AN: 32354

American (AMR) AF: 0.00 AC: 0 AN: 41866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25636

East Asian (EAS) AF: 0.00 AC: 0 AN: 38730

South Asian (SAS) AF: 0.00 AC: 0 AN: 82324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085678

Other (OTH) AF: 0.0000169 AC: 1 AN: 59058

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SLIT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.1
DANN	Benign	0.76
PhyloP100		-0.015

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

Other links and lift over

dbSNP: rs1476281863; hg19: chr4-20258334;