Genetic Variant NM_003062.4:c.4481G>A (chr5-168666545-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_003062.4(SLIT3):c.4481G>A(p.Arg1494Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000936 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SLIT3
NM_003062.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.08

Variant links:

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 links:

ENSG00000254192 (HGNC:):

ENSG00000254192 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLIT3	NM_003062.4 link	c.4481G>A	p.Arg1494Gln	missense_variant	Exon 36 of 36	ENST00000519560.6	NP_003053.2	O75094-1
SLIT3	NM_001271946.2 link	c.4502G>A	p.Arg1501Gln	missense_variant	Exon 36 of 36		NP_001258875.2	O75094-4
SLIT3	XM_017009779.1 link	c.4292G>A	p.Arg1431Gln	missense_variant	Exon 36 of 36		XP_016865268.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLIT3	ENST00000519560.6 link	c.4481G>A	p.Arg1494Gln	missense_variant	Exon 36 of 36	1	NM_003062.4	ENSP00000430333.2	O75094-1
SLIT3	ENST00000332966.8 link	c.4502G>A	p.Arg1501Gln	missense_variant	Exon 36 of 36	1		ENSP00000332164.8	O75094-4
ENSG00000254192	ENST00000520041.1 link	n.433C>T		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000841

AC:

AN:

249592

Hom.:

AF XY:

0.0000518

AC XY:

AN XY:

135080

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000143

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000903

AC:

132

AN:

1461490

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000109

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000125

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000148

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4481G>A (p.R1494Q) alteration is located in exon 36 (coding exon 36) of the SLIT3 gene. This alteration results from a G to A substitution at nucleotide position 4481, causing the arginine (R) at amino acid position 1494 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

0.12

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

.;T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.65

D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.3

.;M;.

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.1

.;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.052

T;T;T

Polyphen

1.0

.;D;.

Vest4

0.55, 0.61

MVP

0.85

MPC

0.68

ClinPred

0.71

GERP RS

5.4

Varity_R

0.51

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over