5-98774155-C-A

Variant names:

• chr5-98774155-C-A
• rs926058865
• NM_001366508.1:c.85C>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001366508.1(RGMB):​c.85C>A​(p.Pro29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000669 in 1,345,702 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: RGMB NM_001366508.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.623

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26657605).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGMB	NM_001366508.1	c.85C>A	p.Pro29Thr	missense_variant	Exon 1 of 3	ENST00000513185.3	NP_001353437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGMB	ENST00000513185.3	c.85C>A	p.Pro29Thr	missense_variant	Exon 1 of 3	2	NM_001366508.1	ENSP00000423256.1
RGMB	ENST00000308234.11	c.208C>A	p.Pro70Thr	missense_variant	Exon 3 of 5	1		ENSP00000308219.7
RGMB	ENST00000434027.2	n.856C>A		non_coding_transcript_exon_variant	Exon 3 of 4	2
RGMB	ENST00000504776.5	n.489C>A		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000669 AC: 9 AN: 1345702 Hom.: 0 Cov.: 31 AF XY: 0.00000904 AC XY: 6 AN XY: 663670

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: 0.00000847

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208C>A (p.P70T) alteration is located in exon 3 (coding exon 2) of the RGMB gene. This alteration results from a C to A substitution at nucleotide position 208, causing the proline (P) at amino acid position 70 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	0.090
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.97	.;L
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.26
Sift	Benign	0.32	T;D
Sift4G	Benign	0.45	T;T
Polyphen		0.042	.;B
Vest4		0.27
MutPred		0.44		.;Gain of loop (P = 0);
MVP		0.59
MPC		0.34
ClinPred		0.14	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.042
gMVP		0.54

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

Other links and lift over

dbSNP: rs926058865; hg19: chr5-98109859;