10-97185599-C-A

Variant names:

• chr10-97185599-C-A
• rs761078698
• NM_003061.3:c.76G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003061.3(SLIT1):​c.76G>T​(p.Ala26Ser) 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 152,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A26P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLIT1 NM_003061.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375
• Publications: 1 publications found

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]

ARHGAP19-SLIT1 (HGNC:48348): (ARHGAP19-SLIT1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring Rho GTPase activating protein 19 (ARHGAP19) and slit homolog 1 (SLIT1) genes on chromosome 10. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

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=0.17738801).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003061.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT1	NM_003061.3	MANE Select	c.76G>T	p.Ala26Ser	missense	Exon 1 of 37	NP_003052.2	O75093-1
	ARHGAP19-SLIT1	NR_037909.1		n.1521-20709G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT1	ENST00000266058.9	TSL:1 MANE Select	c.76G>T	p.Ala26Ser	missense	Exon 1 of 37	ENSP00000266058.4	O75093-1
	ARHGAP19-SLIT1	ENST00000479633.2	TSL:2	n.1475-20709G>T		intron	N/A	ENSP00000473567.1
	SLIT1	ENST00000371070.8	TSL:5	c.76G>T	p.Ala26Ser	missense	Exon 1 of 37	ENSP00000360109.4	Q5T0V0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00000514 AC: 1 AN: 194478 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000209 AC: 3 AN: 1436320 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712708

African (AFR) AF: 0.00 AC: 0 AN: 32808

American (AMR) AF: 0.00 AC: 0 AN: 41162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 38332

South Asian (SAS) AF: 0.00 AC: 0 AN: 83496

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4730

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1101034

Other (OTH) AF: 0.0000169 AC: 1 AN: 59294

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.38
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.087
Sift	Benign	0.097	T
Sift4G	Benign	0.12	T
Polyphen		0.17	B
Vest4		0.12
MutPred		0.47		Loss of MoRF binding (P = 0.1366)
MVP		0.48
MPC		0.40
ClinPred		0.18	T
GERP RS		2.7
PromoterAI		-0.027	Neutral
Varity_R		0.12
gMVP		0.10
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs761078698; hg19: chr10-98945356;