9-137078982-A-C

Variant names:

• chr9-137078982-A-C
• rs985997414
• NM_207309.3:c.677A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_207309.3(UAP1L1):​c.677A>C​(p.Asn226Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N226S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: UAP1L1 NM_207309.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.29
• Publications: 0 publications found

Genes affected

UAP1L1 (HGNC:28082): (UDP-N-acetylglucosamine pyrophosphorylase 1 like 1) Predicted to enable UDP-N-acetylglucosamine diphosphorylase activity. Predicted to be involved in UDP-N-acetylglucosamine biosynthetic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207309.3. 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
	UAP1L1	NM_207309.3	MANE Select	c.677A>C	p.Asn226Thr	missense	Exon 4 of 9	NP_997192.2	Q3KQV9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UAP1L1	ENST00000409858.8	TSL:1 MANE Select	c.677A>C	p.Asn226Thr	missense	Exon 4 of 9	ENSP00000386935.3	Q3KQV9-1
	UAP1L1	ENST00000907215.1		c.677A>C	p.Asn226Thr	missense	Exon 4 of 9	ENSP00000577274.1
	UAP1L1	ENST00000915583.1		c.677A>C	p.Asn226Thr	missense	Exon 4 of 9	ENSP00000585642.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD2 exomes AF: 0.00000444 AC: 1 AN: 225036 AF XY: 0.00000814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000949

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435012 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 713884

African (AFR) AF: 0.00 AC: 0 AN: 31640

American (AMR) AF: 0.00 AC: 0 AN: 35022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24738

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 82242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104420

Other (OTH) AF: 0.00 AC: 0 AN: 59280

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		7.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.87		Gain of phosphorylation at N226 (P = 0.0551)
MVP		0.45
MPC		0.89
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.93
gMVP		0.93
Mutation Taster		=13/87	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: rs985997414; hg19: chr9-139973434;