Genetic Variant SLIT1:p.His1441Gln (chr10-97002201-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003061.3(SLIT1):c.4323C>A(p.His1441Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLIT1
NM_003061.3 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.25724614).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699874

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32524

American (AMR)

AF:

0.00

AC:

AN:

40746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25358

East Asian (EAS)

AF:

0.00

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:

9.21e-7

AC:

AN:

1086078

Other (OTH)

AF:

0.00

AC:

AN:

58240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.035

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

Uncertain

0.97

LIST_S2

Benign

0.49

M_CAP

Benign

0.058

MetaRNN

Benign

0.26

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

0.53

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)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over