3-49721826-A-T

Variant names:

• chr3-49721826-A-T
• NM_021971.4:c.1009T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_021971.4(GMPPB):​c.1009T>A​(p.Tyr337Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,442 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 Lovd as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GMPPB NM_021971.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.21

Genes affected

GMPPB (HGNC:22932): (GDP-mannose pyrophosphorylase B) This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a strand (size 3) in uniprot entity GMPPB_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021971.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant 3-49721826-A-T is Pathogenic according to our data. Variant chr3-49721826-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GMPPB	NM_021971.4	c.1009T>A	p.Tyr337Asn	missense_variant	Exon 9 of 9	ENST00000308388.7	NP_068806.2
GMPPB	NM_013334.4	c.1090T>A	p.Tyr364Asn	missense_variant	Exon 8 of 8		NP_037466.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GMPPB	ENST00000308388.7	c.1009T>A	p.Tyr337Asn	missense_variant	Exon 9 of 9	1	NM_021971.4	ENSP00000311130.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457442 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725316

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Pathogenic	3.7	H;.;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.073	T;D;T
Polyphen		0.40	B;P;B
Vest4		0.94
MutPred		0.58		Loss of phosphorylation at Y337 (P = 0.0295);.;Loss of phosphorylation at Y337 (P = 0.0295);
MVP		0.89
MPC		1.9
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.86
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-49759259;