15-93045323-G-C

Position:

• chr15-93045323-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020211.3(RGMA):​c.1028C>G​(p.Ala343Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGMA NM_020211.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

Genes affected

RGMA (HGNC:30308): (repulsive guidance molecule BMP co-receptor a) This gene encodes a member of the repulsive guidance molecule family. The encoded protein is a glycosylphosphatidylinositol-anchored glycoprotein that functions as an axon guidance protein in the developing and adult central nervous system. This protein may also function as a tumor suppressor in some cancers. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05223587).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGMA	NM_020211.3	c.1028C>G	p.Ala343Gly	missense_variant	4/4	ENST00000329082.12	NP_064596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGMA	ENST00000329082.12	c.1028C>G	p.Ala343Gly	missense_variant	4/4	1	NM_020211.3	ENSP00000330005	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460002 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726292

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2024

The c.1052C>G (p.A351G) alteration is located in exon 4 (coding exon 4) of the RGMA gene. This alteration results from a C to G substitution at nucleotide position 1052, causing the alanine (A) at amino acid position 351 to be replaced by a glycine (G). 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	0.076
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.5
DANN	Benign	0.19
DEOGEN2	Benign	0.038	.;.;.;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.43	.;.;.;.;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.052	T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.5	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.77	T;T;T;T;T;T
Sift4G	Benign	0.75	T;T;T;T;T;T
Vest4		0.063
MutPred		0.39		Loss of helix (P = 0.0104);.;.;.;.;.;
MVP		0.60
MPC		0.22
ClinPred		0.029	T
GERP RS		0.45
gMVP		0.38

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: rs750208375; hg19: chr15-93588553;