chr3-78600303-A-G

Variant names:

• chr3-78600303-A-G
• rs1703096607
• NM_002941.4:c.4751T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_002941.4(ROBO1):​c.4751T>C​(p.Ile1584Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,444,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ROBO1 NM_002941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35
• Publications: 0 publications found

Genes affected

ROBO1 (HGNC:10249): (roundabout guidance receptor 1) Bilateral symmetric nervous systems have special midline structures that establish a partition between the two mirror image halves. Some axons project toward and across the midline in response to long-range chemoattractants emanating from the midline. The product of this gene is a member of the immunoglobulin gene superfamily and encodes an integral membrane protein that functions in axon guidance and neuronal precursor cell migration. This receptor is activated by SLIT-family proteins, resulting in a repulsive effect on glioma cell guidance in the developing brain. A related gene is located at an adjacent region on chromosome 3. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ROBO1 Gene-Disease associations (from GenCC):

• neurooculorenal syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pituitary hormone deficiency, combined or isolated, 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000118 (17/1444124) while in subpopulation EAS AF = 0.000429 (17/39582). AF 95% confidence interval is 0.000273. There are 0 homozygotes in GnomAdExome4. There are 8 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROBO1	NM_002941.4	c.4751T>C	p.Ile1584Thr	missense_variant	Exon 30 of 31	ENST00000464233.6	NP_002932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ROBO1	ENST00000464233.6	c.4751T>C	p.Ile1584Thr	missense_variant	Exon 30 of 31	5	NM_002941.4	ENSP00000420321.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1444124 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 8 AN XY: 719574

African (AFR) AF: 0.00 AC: 0 AN: 33048

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.000429 AC: 17 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096154

Other (OTH) AF: 0.00 AC: 0 AN: 59788

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 13, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;T;.;T;.;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	.;L;.;.;.;.
PhyloP100		7.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	.;N;.;.;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	.;D;.;.;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.66	.;P;.;.;.;.
Vest4		0.96
MutPred		0.36		.;Gain of relative solvent accessibility (P = 0.0023);.;.;.;.;
MVP		0.86
MPC		0.66
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.34
gMVP		0.36
Mutation Taster		=55/45	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

dbSNP: rs1703096607; hg19: chr3-78649453;