5-142006242-G-A

Position:

• chr5-142006242-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005471.5(GNPDA1):​c.311C>T​(p.Thr104Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000014 (0 hom.)
• Consequence: GNPDA1 NM_005471.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50

Genes affected

GNPDA1 (HGNC:4417): (glucosamine-6-phosphate deaminase 1) Glucosamine-6-phosphate deaminase (EC 3.5.99.6) is an allosteric enzyme that catalyzes the reversible conversion of D-glucosamine-6-phosphate into D-fructose-6-phosphate and ammonium (Arreola et al., 2003 [PubMed 12965206]).[supplied by OMIM, Jan 2010]

GNPDA1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1691294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GNPDA1	NM_005471.5	c.311C>T	p.Thr104Ile	missense_variant	4/7	ENST00000311337.11	NP_005462.1
GNPDA1	XM_005268348.2	c.398C>T	p.Thr133Ile	missense_variant	4/7		XP_005268405.1
GNPDA1	XM_006714747.2	c.311C>T	p.Thr104Ile	missense_variant	5/8		XP_006714810.1
GNPDA1	XM_047416582.1	c.311C>T	p.Thr104Ile	missense_variant	5/8		XP_047272538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GNPDA1	ENST00000311337.11	c.311C>T	p.Thr104Ile	missense_variant	4/7	1	NM_005471.5	ENSP00000311876.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461090 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726882

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: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 27, 2023

The c.311C>T (p.T104I) alteration is located in exon 4 (coding exon 3) of the GNPDA1 gene. This alteration results from a C to T substitution at nucleotide position 311, causing the threonine (T) at amino acid position 104 to be replaced by an isoleucine (I). 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	0.17
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.13
DEOGEN2	Benign	0.0039	T;T;T;T;T;T;T;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;.;.;.;D;D;D;D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.19	.;N;N;N;N;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	2.2	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.86	T;T;T;T;T;T;.;.;T
Polyphen		0.0	.;B;B;B;B;.;.;.;.
Vest4		0.65
MutPred		0.51		Loss of catalytic residue at T104 (P = 0.0631);Loss of catalytic residue at T104 (P = 0.0631);Loss of catalytic residue at T104 (P = 0.0631);Loss of catalytic residue at T104 (P = 0.0631);Loss of catalytic residue at T104 (P = 0.0631);Loss of catalytic residue at T104 (P = 0.0631);.;Loss of catalytic residue at T104 (P = 0.0631);Loss of catalytic residue at T104 (P = 0.0631);
MVP		0.39
MPC		0.49
ClinPred		0.75	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.62

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: rs1755801358; hg19: chr5-141385807;