14-52781903-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PS1_Moderate PM2 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PS1: Transcript NM_198066.4 (GNPNAT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-52781903-C-T is Pathogenic according to our data. Variant chr14-52781903-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1302024.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-52781903-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2890085). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNPNAT1	NM_198066.4	c.226G>A	p.Glu76Lys	missense_variant	Exon 4 of 6	ENST00000216410.8	NP_932332.1
GNPNAT1	XM_005268012.4	c.226G>A	p.Glu76Lys	missense_variant	Exon 5 of 7		XP_005268069.1
GNPNAT1	XM_006720238.4	c.226G>A	p.Glu76Lys	missense_variant	Exon 4 of 6		XP_006720301.1
GNPNAT1	XM_047431705.1	c.226G>A	p.Glu76Lys	missense_variant	Exon 5 of 7		XP_047287661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GNPNAT1	ENST00000216410.8	c.226G>A	p.Glu76Lys	missense_variant	Exon 4 of 6	1	NM_198066.4	ENSP00000216410.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Rhizomelic dysplasia, Ain-Naz type Pathogenic:1

Oct 29, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N;.;N;N
REVEL	Benign	0.16
Sift	Benign	0.44	T;.;T;T
Sift4G	Benign	0.57	T;.;T;.
Polyphen		0.38	B;B;.;.
Vest4		0.56
MutPred		0.35		Gain of methylation at E76 (P = 0.0014);Gain of methylation at E76 (P = 0.0014);.;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-53248621;