10-97164876-T-C

Variant names:

• chr10-97164876-T-C
• NM_003061.3:c.212A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_003061.3(SLIT1):​c.212A>G​(p.Asn71Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N71Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLIT1 NM_003061.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26
• Publications: 0 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 4 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.212A>G	p.Asn71Ser	missense	Exon 2 of 37	NP_003052.2	O75093-1
	ARHGAP19-SLIT1	NR_037909.1		n.1535A>G		non_coding_transcript_exon	Exon 12 of 15

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT1	ENST00000266058.9	TSL:1 MANE Select	c.212A>G	p.Asn71Ser	missense	Exon 2 of 37	ENSP00000266058.4	O75093-1
	ARHGAP19-SLIT1	ENST00000479633.2	TSL:2	n.1489A>G		non_coding_transcript_exon	Exon 12 of 15	ENSP00000473567.1
	SLIT1	ENST00000371070.8	TSL:5	c.212A>G	p.Asn71Ser	missense	Exon 2 of 37	ENSP00000360109.4	Q5T0V0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461120 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726854

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111450

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.73		Gain of glycosylation at N71 (P = 0.0879)
MVP		0.91
MPC		1.2
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.74
Mutation Taster		=65/35	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

hg19: chr10-98924633;