5-168708094-A-C

Variant names:

• chr5-168708094-A-C
• rs1383326974
• NM_003062.4:c.2726T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003062.4(SLIT3):​c.2726T>G​(p.Val909Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SLIT3 NM_003062.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

Genes affected

SLIT3 (HGNC:11087): (slit guidance ligand 3) The protein encoded by this gene is secreted, likely interacting with roundabout homolog receptors to effect cell migration. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

SLIT3-AS2 (HGNC:40551): (SLIT3 antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLIT3	NM_003062.4	c.2726T>G	p.Val909Gly	missense_variant	Exon 26 of 36	ENST00000519560.6	NP_003053.2
SLIT3	NM_001271946.2	c.2747T>G	p.Val916Gly	missense_variant	Exon 26 of 36		NP_001258875.2
SLIT3	XM_017009779.1	c.2537T>G	p.Val846Gly	missense_variant	Exon 26 of 36		XP_016865268.1
SLIT3-AS2	NR_130737.1	n.342-343A>C		intron_variant	Intron 1 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLIT3	ENST00000519560.6	c.2726T>G	p.Val909Gly	missense_variant	Exon 26 of 36	1	NM_003062.4	ENSP00000430333.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2726T>G (p.V909G) alteration is located in exon 26 (coding exon 26) of the SLIT3 gene. This alteration results from a T to G substitution at nucleotide position 2726, causing the valine (V) at amino acid position 909 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.9	.;L;.
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-4.8	.;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.91	.;P;.
Vest4		0.51, 0.47
MutPred		0.56		.;Gain of disorder (P = 0.0553);.;
MVP		0.63
MPC		0.55
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.78
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1383326974; hg19: chr5-168135099;