rs1244763154

Variant names:

• chr6-16274479-A-G
• rs1244763154
• NM_006877.4:c.530A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-16274479-A-G
• chr6-16274479-A-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006877.4(GMPR):​c.530A>G​(p.Lys177Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,451,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GMPR NM_006877.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.18
• Publications: 0 publications found

Genes affected

GMPR (HGNC:4376): (guanosine monophosphate reductase) This gene encodes an enzyme that catalyzes the irreversible and NADPH-dependent reductive deamination of GMP to IMP. The protein also functions in the re-utilization of free intracellular bases and purine nucleosides.[provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006877.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPR	NM_006877.4	MANE Select	c.530A>G	p.Lys177Arg	missense	Exon 5 of 9	NP_006868.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GMPR	ENST00000259727.5	TSL:1 MANE Select	c.530A>G	p.Lys177Arg	missense	Exon 5 of 9	ENSP00000259727.4	P36959
	GMPR	ENST00000864761.1		c.530A>G	p.Lys177Arg	missense	Exon 5 of 10	ENSP00000534820.1
	GMPR	ENST00000967431.1		c.623A>G	p.Lys208Arg	missense	Exon 6 of 10	ENSP00000637490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1451462 Hom.: 0 Cov.: 27 AF XY: 0.00000692 AC XY: 5 AN XY: 722888

African (AFR) AF: 0.00 AC: 0 AN: 33292

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000454 AC: 5 AN: 1102478

Other (OTH) AF: 0.00 AC: 0 AN: 60048

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.77
Sift	Benign	0.035	D
Sift4G	Benign	0.099	T
Polyphen		1.0	D
Vest4		0.90
MutPred		0.84		Loss of ubiquitination at K177 (P = 0.027)
MVP		0.94
MPC		0.41
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.95
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1244763154; hg19: chr6-16274710;