10-97001251-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_003061.3(SLIT1):c.4466G>A(p.Arg1489Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,613,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: SLIT1 NM_003061.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.35

Genes affected

SLIT1 (HGNC:11085): (slit guidance ligand 1) Enables Roundabout binding activity. Involved in axon extension involved in axon guidance; motor neuron axon guidance; and negative chemotaxis. Predicted to be located in extracellular region. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SLIT1
• BP4: Computational evidence support a benign effect (MetaRNN=0.059445858).
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLIT1	NM_003061.3	c.4466G>A	p.Arg1489Gln	missense_variant	37/37	ENST00000266058.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLIT1	ENST00000266058.9	c.4466G>A	p.Arg1489Gln	missense_variant	37/37	1	NM_003061.3	P1
SLIT1	ENST00000371070.8	c.4342G>A	p.Gly1448Arg	missense_variant	37/37	5

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000839 AC: 21 AN: 250368 Hom.: 0 AF XY: 0.0000590 AC XY: 8 AN XY: 135592

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000596 AC: 87 AN: 1460818 Hom.: 0 Cov.: 31 AF XY: 0.0000592 AC XY: 43 AN XY: 726708

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74514

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.00

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

Jun 23, 2023

The c.4466G>A (p.R1489Q) alteration is located in exon 37 (coding exon 37) of the SLIT1 gene. This alteration results from a G to A substitution at nucleotide position 4466, causing the arginine (R) at amino acid position 1489 to be replaced by a glutamine (Q). 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	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	19
Dann	Uncertain	0.97
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.28	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D;D;N
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.26
Sift	Benign	0.84	T
Sift4G	Benign	0.13	T
Vest4		0.41
MutPred		0.33		Gain of methylation at G1448 (P = 0.0305);
MVP		0.27
ClinPred		0.024	T
GERP RS		3.3

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

LitVar

Other links and lift over

dbSNP: rs116713666; hg19: chr10-98761008;