3-77622378-G-T

Variant names:

• chr3-77622378-G-T
• NM_001395656.1:c.3718G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001395656.1(ROBO2):​c.3718G>T​(p.Ala1240Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A1240T) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ROBO2 NM_001395656.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-77622378-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.27818403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO2	NM_001395656.1	c.3718G>T	p.Ala1240Ser	missense_variant	Exon 24 of 28	ENST00000696593.1	NP_001382585.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO2	ENST00000696593.1	c.3718G>T	p.Ala1240Ser	missense_variant	Exon 24 of 28		NM_001395656.1	ENSP00000512738.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0042	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;D;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	.;L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.18	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.051	T;D;D;.
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0020, 0.073	.;B;B;.
Vest4		0.20
MutPred		0.21		.;Gain of glycosylation at T1240 (P = 0.0513);Gain of glycosylation at T1240 (P = 0.0513);.;
MVP		0.51
MPC		0.20
ClinPred		0.67	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.13

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-77671529;