Genetic Variant SLIT1:p.His1441Gln (chr10-97002201-G-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_003061.3(SLIT1):c.4323C>G(p.His1441Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000567 in 1,570,310 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

SLIT1
NM_003061.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

Publications

0 publications found

Variant links:

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]

SLIT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.0887 (below the threshold of 3.09). Trascript score misZ: 3.2604 (above the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.13314542).

BS2

High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLIT1	NM_003061.3 link	c.4323C>G	p.His1441Gln	missense_variant	Exon 36 of 37	ENST00000266058.9	NP_003052.2	O75093-1A6H8V1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLIT1	ENST00000266058.9 link	c.4323C>G	p.His1441Gln	missense_variant	Exon 36 of 37	1	NM_003061.3	ENSP00000266058.4		O75093-1
SLIT1	ENST00000371070.8 link	c.4242+81C>G		intron_variant	Intron 36 of 36	5		ENSP00000360109.4		Q5T0V0

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000392

AC:

AN:

204024

AF XY:

0.0000269

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.0000667

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000664

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1418140

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

699874

show subpopulations

African (AFR)

AF:

0.000246

AC:

AN:

32524

American (AMR)

AF:

0.0000491

AC:

AN:

40746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25358

East Asian (EAS)

AF:

0.0000797

AC:

AN:

37656

South Asian (SAS)

AF:

0.00

AC:

AN:

82488

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4624

European-Non Finnish (NFE)

AF:

0.0000470

AC:

AN:

1086078

Other (OTH)

AF:

0.0000343

AC:

AN:

58240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000151

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000125

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4323C>G (p.H1441Q) alteration is located in exon 36 (coding exon 36) of the SLIT1 gene. This alteration results from a C to G substitution at nucleotide position 4323, causing the histidine (H) at amino acid position 1441 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

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.045

Eigen

Benign

-0.21

Eigen_PC

Benign

0.032

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.49

M_CAP

Benign

0.054

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.69

PhyloP100

4.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.3

REVEL

Benign

0.16

Sift

Benign

0.17

Sift4G

Benign

0.32

Polyphen

0.0020

Vest4

0.16

MutPred

0.36

Gain of methylation at K1438 (P = 0.114);

MVP

0.60

MPC

0.50

ClinPred

0.048

GERP RS

4.9

Varity_R

0.12

gMVP

0.078

Mutation Taster

=75/25

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

10-97002201-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over