X-7105631-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_012080.5(PUDP):c.269C>T(p.Ala90Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,202,050 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 369 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A90A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., 17 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (0 hom. 352 hem.)
• Consequence: PUDP NM_012080.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.116

Genes affected

PUDP (HGNC:16818): (pseudouridine 5'-phosphatase) This gene encodes a member of the haloacid dehalogenase-like (HAD) hydrolase superfamily. The encoded protein has no known biological function. This gene has a pseudogene on chromosome 1. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029144347).
• BS2: High Hemizygotes in GnomAd at 17 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUDP	NM_012080.5	c.269C>T	p.Ala90Val	missense_variant	2/4	ENST00000381077.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUDP	ENST00000381077.10	c.269C>T	p.Ala90Val	missense_variant	2/4	1	NM_012080.5	P1

Frequencies

GnomAD3 genomes AF: 0.000484 AC: 54 AN: 111625 Hom.: 0 Cov.: 23 AF XY: 0.000503 AC XY: 17 AN XY: 33813

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000378

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000827

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000461 AC: 79 AN: 171468 Hom.: 0 AF XY: 0.000413 AC XY: 24 AN XY: 58120

Gnomad AFR exome AF: 0.0000826

Gnomad AMR exome AF: 0.0000765

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000365

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000844

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000999 AC: 1089 AN: 1090374 Hom.: 0 Cov.: 28 AF XY: 0.000986 AC XY: 352 AN XY: 357048

Gnomad4 AFR exome AF: 0.0000763

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000264

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.000853

GnomAD4 genome AF: 0.000484 AC: 54 AN: 111676 Hom.: 0 Cov.: 23 AF XY: 0.000502 AC XY: 17 AN XY: 33874

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000285

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000379

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000827

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000760 Hom.: 7

Bravo AF: 0.000484

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00242 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00123 AC: 8

ExAC AF: 0.000447 AC: 54

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

Apr 07, 2022

The c.338C>T (p.A113V) alteration is located in exon 3 (coding exon 3) of the PUDP gene. This alteration results from a C to T substitution at nucleotide position 338, causing the alanine (A) at amino acid position 113 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.35
Dann	Benign	0.96
DEOGEN2	Benign	0.049	T;.;.;.
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.029	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.25	T;T;T;.
Polyphen		0.17	B;.;D;P
Vest4		0.095
MVP		0.13
MPC		0.066
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.13
gMVP		0.42

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: rs201478475; hg19: chrX-7023672;