Genetic Variant NM_001366508.1:c.116G>C (chr5-98774186-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001366508.1(RGMB):c.116G>C(p.Ser39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

RGMB
NM_001366508.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Variant links:

Genes affected

RGMB (HGNC:26896): (repulsive guidance molecule BMP co-receptor b) RGMB is a glycosylphosphatidylinositol (GPI)-anchored member of the repulsive guidance molecule family (see RGMA, MIM 607362) and contributes to the patterning of the developing nervous system (Samad et al., 2005 [PubMed 15671031]).[supplied by OMIM, Apr 2009]

RGMB links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29495353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGMB	NM_001366508.1 link	c.116G>C	p.Ser39Thr	missense_variant	Exon 1 of 3	ENST00000513185.3	NP_001353437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RGMB	ENST00000513185.3 link	c.116G>C	p.Ser39Thr	missense_variant	Exon 1 of 3	2	NM_001366508.1	ENSP00000423256.1	Q6NW40
RGMB	ENST00000308234.11 link	c.239G>C	p.Ser80Thr	missense_variant	Exon 3 of 5	1		ENSP00000308219.7	J3KNF6
RGMB	ENST00000434027.2 link	n.887G>C		non_coding_transcript_exon_variant	Exon 3 of 4	2
RGMB	ENST00000504776.5 link	n.520G>C		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.239G>C (p.S80T) alteration is located in exon 3 (coding exon 2) of the RGMB gene. This alteration results from a G to C substitution at nucleotide position 239, causing the serine (S) at amino acid position 80 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.11

.;T

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.39

T;T

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.90

.;L

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.31

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.81

T;T

Sift4G

Benign

0.69

T;T

Polyphen

0.13

.;B

Vest4

0.23

MutPred

0.71

.;Gain of helix (P = 0.1736);

MVP

0.67

MPC

0.27

ClinPred

0.20

GERP RS

3.1

Varity_R

0.13

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over