5-168666648-G-A

Variant names:

• chr5-168666648-G-A
• rs142603158
• NM_003062.4:c.4378C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003062.4(SLIT3):​c.4378C>T​(p.Arg1460Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000675 in 1,614,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R1460H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: SLIT3 NM_003062.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• congenital diaphragmatic hernia

  Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia

ENSG00000254192 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23208293).
• BS2: High AC in GnomAd4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003062.4. 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
	SLIT3	NM_003062.4	MANE Select	c.4378C>T	p.Arg1460Cys	missense	Exon 36 of 36	NP_003053.2	O75094-1
	SLIT3	NM_001271946.2		c.4399C>T	p.Arg1467Cys	missense	Exon 36 of 36	NP_001258875.2	O75094-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLIT3	ENST00000519560.6	TSL:1 MANE Select	c.4378C>T	p.Arg1460Cys	missense	Exon 36 of 36	ENSP00000430333.2	O75094-1
	SLIT3	ENST00000332966.8	TSL:1	c.4399C>T	p.Arg1467Cys	missense	Exon 36 of 36	ENSP00000332164.8	O75094-4
	ENSG00000254192	ENST00000520041.1	TSL:5	n.536G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000100 AC: 25 AN: 249100 AF XY: 0.000104

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000718

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34 AN XY: 727236

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1112008

Other (OTH) AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74330

African (AFR) AF: 0.000579 AC: 24 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000967 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Uncertain	0.50
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.4
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.021	D
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.54
MVP		0.54
MPC		1.1
ClinPred		0.13	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.68
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs142603158; hg19: chr5-168093653;