6-16238729-C-A

Variant names:

• chr6-16238729-C-A
• NM_006877.4:c.36C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006877.4(GMPR):​c.36C>A​(p.Phe12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000768 in 1,301,726 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: 7.7e-7 (0 hom.)
• Consequence: GMPR NM_006877.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0470
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

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.36C>A	p.Phe12Leu	missense	Exon 1 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.36C>A	p.Phe12Leu	missense	Exon 1 of 9	ENSP00000259727.4	P36959
	GMPR	ENST00000864761.1		c.36C>A	p.Phe12Leu	missense	Exon 1 of 10	ENSP00000534820.1
	GMPR	ENST00000967431.1		c.36C>A	p.Phe12Leu	missense	Exon 1 of 10	ENSP00000637490.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.68e-7 AC: 1 AN: 1301726 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 641428

African (AFR) AF: 0.00 AC: 0 AN: 27464

American (AMR) AF: 0.00 AC: 0 AN: 29108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22638

East Asian (EAS) AF: 0.00 AC: 0 AN: 29280

South Asian (SAS) AF: 0.00 AC: 0 AN: 67360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4836

European-Non Finnish (NFE) AF: 9.77e-7 AC: 1 AN: 1023160

Other (OTH) AF: 0.00 AC: 0 AN: 52440

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	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		0.047
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.72		Loss of sheet (P = 0.0037)
MVP		0.95
MPC		0.44
ClinPred		1.0	D
GERP RS		2.5
PromoterAI		-0.12	Neutral
Varity_R		0.91
gMVP		0.85
Mutation Taster		=36/64	disease causing

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

Other links and lift over

hg19: chr6-16238960;