rs368123079

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001257096.2(PAX1):c.1282+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,509,864 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 21 hom. )

Consequence

PAX1
NM_001257096.2 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -3.28

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

otofaciocervical syndrome 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

PAX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 20-21709456-A-C is Benign according to our data. Variant chr20-21709456-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445455.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00313 (477/152272) while in subpopulation NFE AF = 0.00559 (380/68006). AF 95% confidence interval is 0.00512. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2 link	c.1282+12A>C		intron_variant	Intron 4 of 4	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5 link	c.1282+12A>C		intron_variant	Intron 4 of 4		NP_006183.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
PAX1	ENST00000613128.5 link	c.1282+12A>C	intron_variant	Intron 4 of 4	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6 link	c.1282+12A>C	intron_variant	Intron 4 of 4	5		ENSP00000381499.2
PAX1	ENST00000444366.2 link	c.1210+12A>C	intron_variant	Intron 3 of 3	2		ENSP00000410355.2
PAX1	ENST00000485038.1 link	n.*179A>C	downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

477

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00261

AC:

308

AN:

118064

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.000560

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.000167

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000862

Gnomad NFE exome

AF:

0.00574

Gnomad OTH exome

AF:

0.00222

GnomAD4 exome

AF:

0.00521

AC:

7068

AN:

1357592

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

3417

AN XY:

668084

show subpopulations

African (AFR)

AF:

0.000848

AC:

AN:

30674

American (AMR)

AF:

0.00111

AC:

AN:

32362

Ashkenazi Jewish (ASJ)

AF:

0.0000860

AC:

AN:

23246

East Asian (EAS)

AF:

0.00

AC:

AN:

35470

South Asian (SAS)

AF:

0.000186

AC:

AN:

75442

European-Finnish (FIN)

AF:

0.00159

AC:

AN:

35268

Middle Eastern (MID)

AF:

0.000502

AC:

AN:

3986

European-Non Finnish (NFE)

AF:

0.00631

AC:

6720

AN:

1064642

Other (OTH)

AF:

0.00375

AC:

212

AN:

56502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

350

700

1051

1401

1751

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

260

520

780

1040

1300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00313

AC:

477

AN:

152272

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

231

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41570

American (AMR)

AF:

0.00203

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00559

AC:

380

AN:

68006

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.00288

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PAX1: BS2 -

Jun 01, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1282+12A>C variant in PAX1 is classified as likely benign because it is not located within the splice consensus sequence and computational splice prediction tools do not predict an impact on splicing. It has also been identified in 0.558% (339/60720) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and in one individual with Klippel-Feil syndrome (McGaughran 2003 PMID: 12774041). ACMG/AMP Criteria applied: BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.025

(source)

DANN

Benign

0.59

PhyloP100

-3.3

Mutation Taster

=21/79

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over