chr14-52781903-C-T

Variant names:

• chr14-52781903-C-T
• rs2139964469
• NM_198066.4:c.226G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_198066.4(GNPNAT1):​c.226G>A​(p.Glu76Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E76G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNPNAT1 NM_198066.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.81
• Publications: 2 publications found

Genes affected

GNPNAT1 (HGNC:19980): (glucosamine-phosphate N-acetyltransferase 1) Enables identical protein binding activity. Predicted to be involved in UDP-N-acetylglucosamine biosynthetic process. Predicted to act upstream of or within cellular response to leukemia inhibitory factor. Predicted to be located in late endosome. Predicted to be active in Golgi apparatus; endoplasmic reticulum; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

GNPNAT1 Gene-Disease associations (from GenCC):

• osteochondrodysplasia

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.3296 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to osteochondrodysplasia.
• PP5: Variant 14-52781903-C-T is Pathogenic according to our data. Variant chr14-52781903-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1302024.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2890085). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198066.4. 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
	GNPNAT1	NM_198066.4	MANE Select	c.226G>A	p.Glu76Lys	missense	Exon 4 of 6	NP_932332.1	Q96EK6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNPNAT1	ENST00000216410.8	TSL:1 MANE Select	c.226G>A	p.Glu76Lys	missense	Exon 4 of 6	ENSP00000216410.3	Q96EK6
	GNPNAT1	ENST00000650397.1		c.226G>A	p.Glu76Lys	missense	Exon 4 of 7	ENSP00000496934.1	Q96EK6
	GNPNAT1	ENST00000875202.1		c.226G>A	p.Glu76Lys	missense	Exon 4 of 7	ENSP00000545261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Rhizomelic dysplasia, Ain-Naz type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.44	T
Sift4G	Benign	0.57	T
Polyphen		0.38	B
Vest4		0.56
MutPred		0.35		Gain of methylation at E76 (P = 0.0014)
MVP		0.60
MPC		0.45
ClinPred		0.74	D
GERP RS		5.5
Varity_R		0.43
gMVP		0.89
Mutation Taster		=32/68	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: rs2139964469; hg19: chr14-53248621;