chrX-7148071-T-C

Position:

• chrX-7148071-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.43A>G​(p.Met15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 1,135,641 control chromosomes in the GnomAD database, including 1 homozygotes. There are 337 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., 23 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (1 hom. 314 hem.)
• Consequence: PUDP NM_012080.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.127

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]

STS (HGNC:11425): (steroid sulfatase) This gene encodes a multi-pass membrane protein that is localized to the endoplasmic reticulum. It belongs to the sulfatase family and hydrolyzes several 3-beta-hydroxysteroid sulfates, which serve as metabolic precursors for estrogens, androgens, and cholesterol. Mutations in this gene are associated with X-linked ichthyosis (XLI). Alternatively spliced transcript variants resulting from the use of different promoters have been described for this gene (PMID:17601726). [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03861448).
• BS2: High Hemizygotes in GnomAd4 at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PUDP	NM_012080.5	c.43A>G	p.Met15Val	missense_variant	1/4	ENST00000381077.10
STS	NM_001320752.2	c.-146T>C		5_prime_UTR_variant	1/11	ENST00000674429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PUDP	ENST00000381077.10	c.43A>G	p.Met15Val	missense_variant	1/4	1	NM_012080.5	P1
STS	ENST00000674429.1	c.-146T>C		5_prime_UTR_variant	1/11		NM_001320752.2	P1

Frequencies

GnomAD3 genomes AF: 0.000636 AC: 70 AN: 110091 Hom.: 0 Cov.: 23 AF XY: 0.000704 AC XY: 23 AN XY: 32665

Gnomad AFR AF: 0.0000656

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00298

Gnomad MID AF: 0.00435

Gnomad NFE AF: 0.000879

Gnomad OTH AF: 0.000672

GnomAD3 exomes AF: 0.000724 AC: 67 AN: 92530 Hom.: 0 AF XY: 0.000969 AC XY: 29 AN XY: 29942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000824

Gnomad FIN exome AF: 0.00305

Gnomad NFE exome AF: 0.000817

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00101 AC: 1035 AN: 1025498 Hom.: 1 Cov.: 28 AF XY: 0.000951 AC XY: 314 AN XY: 330224

Gnomad4 AFR exome AF: 0.000226

Gnomad4 AMR exome AF: 0.000118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00324

Gnomad4 NFE exome AF: 0.00108

Gnomad4 OTH exome AF: 0.000792

GnomAD4 genome AF: 0.000636 AC: 70 AN: 110143 Hom.: 0 Cov.: 23 AF XY: 0.000703 AC XY: 23 AN XY: 32725

Gnomad4 AFR AF: 0.0000655

Gnomad4 AMR AF: 0.000283

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00298

Gnomad4 NFE AF: 0.000879

Gnomad4 OTH AF: 0.000663

Alfa AF: 0.000256 Hom.: 3

Bravo AF: 0.000495

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000593 AC: 3

ExAC AF: 0.000157 AC: 7

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 25, 2022

The c.43A>G (p.M15V) alteration is located in exon 1 (coding exon 1) of the PUDP gene. This alteration results from a A to G substitution at nucleotide position 43, causing the methionine (M) at amino acid position 15 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T;.;.;.;.
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.91	D;D;T;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.039	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M;M;M;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D;D;D;D;D
REVEL	Benign	0.13
Sift	Benign	0.034	D;T;D;D;D
Sift4G	Benign	0.11	T;T;T;D;.
Polyphen		0.12	B;B;.;B;B
Vest4		0.42
MVP		0.48
MPC		0.077
ClinPred		0.10	T
GERP RS		-0.31
Varity_R		0.65
gMVP		0.62

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: rs374016250; hg19: chrX-7066112;