3-155870895-A-C

Variant names:

• chr3-155870895-A-C
• rs1753888166
• NM_003875.3:c.25A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_003875.3(GMPS):​c.25A>C​(p.Lys9Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,351,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GMPS NM_003875.3 missense, splice_region
• Scores: Splicing: ADA: 0.01297
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

Genes affected

GMPS (HGNC:4378): (guanine monophosphate synthase) In the de novo synthesis of purine nucleotides, IMP is the branch point metabolite at which point the pathway diverges to the synthesis of either guanine or adenine nucleotides. In the guanine nucleotide pathway, there are 2 enzymes involved in converting IMP to GMP, namely IMP dehydrogenase (IMPD1), which catalyzes the oxidation of IMP to XMP, and GMP synthetase, which catalyzes the amination of XMP to GMP. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity GUAA_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14125535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPS	NM_003875.3	c.25A>C	p.Lys9Gln	missense_variant, splice_region_variant	Exon 1 of 16	ENST00000496455.7	NP_003866.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPS	ENST00000496455.7	c.25A>C	p.Lys9Gln	missense_variant, splice_region_variant	Exon 1 of 16	1	NM_003875.3	ENSP00000419851.1
GMPS	ENST00000295920.7	c.25A>C	p.Lys9Gln	missense_variant, splice_region_variant	Exon 1 of 14	2		ENSP00000295920.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1351024 Hom.: 0 Cov.: 30 AF XY: 0.00000300 AC XY: 2 AN XY: 667150

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: 0.00000283

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25A>C (p.K9Q) alteration is located in exon 1 (coding exon 1) of the GMPS gene. This alteration results from a A to C substitution at nucleotide position 25, causing the lysine (K) at amino acid position 9 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.079
Sift	Benign	0.20	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.15	B;.
Vest4		0.34
MutPred		0.26		Loss of ubiquitination at K9 (P = 0.0022);Loss of ubiquitination at K9 (P = 0.0022);
MVP		0.38
MPC		0.40
ClinPred		0.35	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.14
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.013
dbscSNV1_RF	Benign	0.12
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: rs1753888166; hg19: chr3-155588684;