14-52781810-G-A

Variant names:

• chr14-52781810-G-A
• rs766094776
• NM_198066.4:c.319C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_198066.4(GNPNAT1):​c.319C>T​(p.His107Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GNPNAT1 NM_198066.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• Publications: 0 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.

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.319C>T	p.His107Tyr	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.319C>T	p.His107Tyr	missense	Exon 4 of 6	ENSP00000216410.3	Q96EK6
	GNPNAT1	ENST00000650397.1		c.319C>T	p.His107Tyr	missense	Exon 4 of 7	ENSP00000496934.1	Q96EK6
	GNPNAT1	ENST00000875202.1		c.319C>T	p.His107Tyr	missense	Exon 4 of 7	ENSP00000545261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452272 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 2 AN XY: 722382

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33016

American (AMR) AF: 0.0000464 AC: 2 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39150

South Asian (SAS) AF: 0.00 AC: 0 AN: 84598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52876

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4334

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109276

Other (OTH) AF: 0.00 AC: 0 AN: 59918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	Benign	0.23
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	N
PhyloP100		7.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Benign	0.071	T
Sift4G	Benign	1.0	T
Polyphen		0.85	P
Vest4		0.42
MutPred		0.48		Loss of catalytic residue at I105 (P = 0.1522)
MVP		0.60
MPC		0.46
ClinPred		0.69	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.88
Mutation Taster		=25/75	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

dbSNP: rs766094776; hg19: chr14-53248528;