Genetic Variant PAX1:p.Trp16Cys (chr20-21705760-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001257096.2(PAX1):c.48G>T(p.Trp16Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000317 in 1,262,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAX1
NM_001257096.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.71

Variant links:

Genes affected

PAX1 (HGNC:8615): (paired box 1) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. This gene plays a role in pattern formation during embryogenesis and may be essential for development of the vertebral column. This gene is silenced by methylation in ovarian and cervical cancers and may be a tumor suppressor gene. Mutations in this gene are also associated with vertebral malformations. [provided by RefSeq, Mar 2012]

PAX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2 link	c.48G>T	p.Trp16Cys	missense_variant	Exon 1 of 5	ENST00000613128.5	NP_001244025.1	A0A087WXV5
PAX1	NM_006192.5 link	c.48G>T	p.Trp16Cys	missense_variant	Exon 1 of 5		NP_006183.2	P15863-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX1	ENST00000613128.5 link	c.48G>T	p.Trp16Cys	missense_variant	Exon 1 of 5	1	NM_001257096.2	ENSP00000481334.1		A0A087WXV5
PAX1	ENST00000398485.6 link	c.48G>T	p.Trp16Cys	missense_variant	Exon 1 of 5	5		ENSP00000381499.2		P15863-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151380

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

20060

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000270

AC:

AN:

1111442

Hom.:

Cov.:

AF XY:

0.00000189

AC XY:

AN XY:

529700

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22932

American (AMR)

AF:

0.00

AC:

AN:

8404

Ashkenazi Jewish (ASJ)

AF:

0.0000701

AC:

AN:

14270

East Asian (EAS)

AF:

0.00

AC:

AN:

26806

South Asian (SAS)

AF:

0.00

AC:

AN:

20584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3270

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

935240

Other (OTH)

AF:

0.0000450

AC:

AN:

44398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151380

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73876

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41362

American (AMR)

AF:

0.00

AC:

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10464

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67642

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 21, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.48G>T (p.W16C) alteration is located in exon 1 (coding exon 1) of the PAX1 gene. This alteration results from a G to T substitution at nucleotide position 48, causing the tryptophan (W) at amino acid position 16 to be replaced by a cysteine (C). 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

0.49

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.62

T;T

M_CAP

Pathogenic

0.87

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

0.90

L;.

PhyloP100

3.7

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.83

N;.

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;.

Vest4

0.47

MutPred

0.48

Loss of MoRF binding (P = 0.0169);Loss of MoRF binding (P = 0.0169);

MVP

0.67

MPC

2.8

ClinPred

0.71

GERP RS

4.5

PromoterAI

0.023

Neutral

(source)

Varity_R

0.36

gMVP

0.28

Mutation Taster

=74/26

polymorphism

(source)

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

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20-21705760-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over