5-168666647-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003062.4(SLIT3):c.4379G>A(p.Arg1460His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 1,614,168 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1460C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: SLIT3 NM_003062.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.10

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009153724).
• BP6: Variant 5-168666647-C-T is Benign according to our data. Variant chr5-168666647-C-T is described in ClinVar as [Benign]. Clinvar id is 771388.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLIT3	NM_003062.4	c.4379G>A	p.Arg1460His	missense_variant	36/36	ENST00000519560.6
SLIT3	NM_001271946.2	c.4400G>A	p.Arg1467His	missense_variant	36/36
SLIT3	XM_017009779.1	c.4190G>A	p.Arg1397His	missense_variant	36/36

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLIT3	ENST00000519560.6	c.4379G>A	p.Arg1460His	missense_variant	36/36	1	NM_003062.4	A1
SLIT3	ENST00000332966.8	c.4400G>A	p.Arg1467His	missense_variant	36/36	1		P4
	ENST00000520041.1	n.535C>T		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00175 AC: 435 AN: 249094 Hom.: 5 AF XY: 0.00126 AC XY: 170 AN XY: 134842

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000446 AC: 652 AN: 1461862 Hom.: 4 Cov.: 32 AF XY: 0.000389 AC XY: 283 AN XY: 727236

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00919

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000672

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000140

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74466

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.000918

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00152 AC: 184

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D;D;D
MetaRNN	Benign	0.0092	T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.98	.;D;.
Vest4		0.40, 0.54
MVP		0.67
MPC		0.97
ClinPred		0.061	T
GERP RS		5.1
Varity_R		0.083
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs138032051; hg19: chr5-168093652; COSMIC: COSV60625461;