Variant 5-98774144-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001366508.1(RGMB):c.74T>C(p.Leu25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,489,342 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

RGMB
NM_001366508.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.285

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18636066).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGMB	NM_001366508.1 linkuse as main transcript	c.74T>C	p.Leu25Pro	missense_variant	1/3	ENST00000513185.3	NP_001353437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
RGMB	ENST00000513185.3 linkuse as main transcript	c.74T>C	p.Leu25Pro	missense_variant	1/3	2	NM_001366508.1	ENSP00000423256
RGMB	ENST00000308234.11 linkuse as main transcript	c.197T>C	p.Leu66Pro	missense_variant	3/5	1		ENSP00000308219	P1
RGMB	ENST00000434027.2 linkuse as main transcript	n.845T>C		non_coding_transcript_exon_variant	3/4	2
RGMB	ENST00000504776.5 linkuse as main transcript	n.478T>C		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000942

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000666

AC:

AN:

90026

Hom.:

AF XY:

0.0000792

AC XY:

AN XY:

50486

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000102

AC:

137

AN:

1337242

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

659590

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000620

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000134

Gnomad4 FIN exome

AF:

0.0000597

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.000197

GnomAD4 genome

AF:

0.000131

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.197T>C (p.L66P) alteration is located in exon 3 (coding exon 2) of the RGMB gene. This alteration results from a T to C substitution at nucleotide position 197, causing the leucine (L) at amino acid position 66 to be replaced by a proline (P). 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

0.049

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.13

.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.36

T;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.14

.;N

MutationTaster

Benign

0.99

D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.22

Sift

Benign

0.092

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.0

.;B

Vest4

0.11

MutPred

0.37

.;Gain of glycosylation at L25 (P = 0.0023);

MVP

0.62

MPC

0.38

ClinPred

0.045

GERP RS

-2.0

Varity_R

0.14

gMVP

0.39

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