Genetic Variant SLIT3:p.His901Gln (chr5-168710911-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003062.4(SLIT3):c.2703C>A(p.His901Gln) 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 152,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLIT3
NM_003062.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.205

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:

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

SLIT3-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22303653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLIT3	NM_003062.4 link	c.2703C>A	p.His901Gln	missense_variant	Exon 25 of 36	ENST00000519560.6	NP_003053.2	O75094-1
SLIT3	NM_001271946.2 link	c.2703C>A	p.His901Gln	missense_variant	Exon 25 of 36		NP_001258875.2	O75094-4
SLIT3	XM_017009779.1 link	c.2514C>A	p.His838Gln	missense_variant	Exon 25 of 36		XP_016865268.1
SLIT3-AS2	NR_130737.1 link	n.698+711G>T		intron_variant	Intron 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLIT3	ENST00000519560.6 link	c.2703C>A	p.His901Gln	missense_variant	Exon 25 of 36	1	NM_003062.4	ENSP00000430333.2	O75094-1
SLIT3	ENST00000332966.8 link	c.2703C>A	p.His901Gln	missense_variant	Exon 25 of 36	1		ENSP00000332164.8	O75094-4
SLIT3-AS2	ENST00000522615.1 link	n.2227+711G>T		intron_variant	Intron 2 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1396662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687792

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2703C>A (p.H901Q) alteration is located in exon 25 (coding exon 25) of the SLIT3 gene. This alteration results from a C to A substitution at nucleotide position 2703, causing the histidine (H) at amino acid position 901 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

0.11

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.096

.;T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.67

.;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.0

.;N;N

REVEL

Benign

0.11

Sift

Benign

0.15

.;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0060

.;B;.

Vest4

0.31, 0.37

MutPred

0.42

.;Loss of ubiquitination at K906 (P = 0.1016);Loss of ubiquitination at K906 (P = 0.1016);

MVP

0.62

MPC

0.29

ClinPred

0.17

GERP RS

3.9

Varity_R

0.11

gMVP

0.51

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

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