X-7050367-T-C

Variant summary

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

The NM_012080.5(PUDP):c.616A>G(p.Lys206Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000128 in 1,097,751 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 3 hem.)
• Consequence: PUDP NM_012080.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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=0.039750755).
• BS2: High Hemizygotes in GnomAdExome at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUDP	NM_012080.5	c.616A>G	p.Lys206Glu	missense_variant	4/4	ENST00000381077.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUDP	ENST00000381077.10	c.616A>G	p.Lys206Glu	missense_variant	4/4	1	NM_012080.5	P1
PUDP	ENST00000424830.6	c.685A>G	p.Lys229Glu	missense_variant	5/5	3
PUDP	ENST00000412827.6	c.487A>G	p.Lys163Glu	missense_variant	4/4	2
PUDP	ENST00000655425.1	c.204+26853A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000663 AC: 12 AN: 180944 Hom.: 0 AF XY: 0.0000299 AC XY: 2 AN XY: 66988

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000440

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097751 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3 AN XY: 363189

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

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

Jun 22, 2021

The c.685A>G (p.K229E) alteration is located in exon 5 (coding exon 5) of the PUDP gene. This alteration results from a A to G substitution at nucleotide position 685, causing the lysine (K) at amino acid position 229 to be replaced by a glutamic acid (E). 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	0.21
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	8.0
Dann	Benign	0.20
DEOGEN2	Benign	0.032	T;.;.
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.82	T;D;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.040	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.34	N;N;N
REVEL	Benign	0.025
Sift	Benign	0.95	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.042
MutPred		0.38		Loss of ubiquitination at K206 (P = 0.0148);.;.;
MVP		0.20
MPC		0.091
ClinPred		0.032	T
GERP RS		2.0
Varity_R		0.15
gMVP		0.54

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: rs752120998; hg19: chrX-6968408;