3-75937535-A-G

Position:

• chr3-75937535-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001378191.1(ROBO2):​c.42A>G​(p.Thr14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000561 in 1,426,788 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 Benign (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: ROBO2 NM_001378191.1 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.776

Genes affected

ROBO2 (HGNC:10250): (roundabout guidance receptor 2) The protein encoded by this gene belongs to the ROBO family, part of the immunoglobulin superfamily of proteins that are highly conserved from fly to human. The encoded protein is a transmembrane receptor for the slit homolog 2 protein and functions in axon guidance and cell migration. Mutations in this gene are associated with vesicoureteral reflux, characterized by the backward flow of urine from the bladder into the ureters or the kidney. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-75937535-A-G is Benign according to our data. Variant chr3-75937535-A-G is described in ClinVar as [Benign]. Clinvar id is 3059790.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-75937535-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.776 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROBO2	NM_001378191.1	c.42A>G	p.Thr14=	synonymous_variant	2/30		NP_001365120.1
ROBO2	NM_001378190.1	c.42A>G	p.Thr14=	synonymous_variant	2/29		NP_001365119.1
ROBO2	NM_001378195.1	c.42A>G	p.Thr14=	synonymous_variant	2/29		NP_001365124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696630.1	c.42A>G	p.Thr14=	synonymous_variant	2/30			ENSP00000512767
ROBO2	ENST00000696629.1	c.42A>G	p.Thr14=	synonymous_variant	2/29			ENSP00000512766
ROBO2	ENST00000471893.2	c.42A>G	p.Thr14=	synonymous_variant	2/29	4		ENSP00000418190

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000561 AC: 8 AN: 1426788 Hom.: 0 Cov.: 30 AF XY: 0.00000564 AC XY: 4 AN XY: 708770

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000727

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.279 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ROBO2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.15
DANN	Benign	0.34

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs62269817; hg19: chr3-75986686; COSMIC: COSV72212998;