chr20-21705744-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001257096.2(PAX1):c.32C>T(p.Ala11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,255,368 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0084 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00084 ( 12 hom. )

Consequence

PAX1
NM_001257096.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.561

Publications

4 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

PAX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055606365).

BP6

Variant 20-21705744-C-T is Benign according to our data. Variant chr20-21705744-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00844 (1278/151448) while in subpopulation AFR AF = 0.0296 (1225/41412). AF 95% confidence interval is 0.0282. There are 19 homozygotes in GnomAd4. There are 619 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257096.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX1	NM_001257096.2	MANE Select	c.32C>T	p.Ala11Val	missense	Exon 1 of 5	NP_001244025.1	A0A087WXV5
	PAX1	NM_006192.5		c.32C>T	p.Ala11Val	missense	Exon 1 of 5	NP_006183.2	P15863-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX1	ENST00000613128.5	TSL:1 MANE Select	c.32C>T	p.Ala11Val	missense	Exon 1 of 5	ENSP00000481334.1	A0A087WXV5
	PAX1	ENST00000398485.6	TSL:5	c.32C>T	p.Ala11Val	missense	Exon 1 of 5	ENSP00000381499.2	P15863-1

Frequencies

GnomAD3 genomes

AF:

0.00828

AC:

1253

AN:

151342

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00433

GnomAD2 exomes

AF:

0.00246

AC:

AN:

21958

AF XY:

0.00245

show subpopulations

Gnomad AFR exome

AF:

0.0340

Gnomad AMR exome

AF:

0.00368

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000841

AC:

928

AN:

1103920

Hom.:

Cov.:

AF XY:

0.000804

AC XY:

422

AN XY:

524630

show subpopulations

African (AFR)

AF:

0.0299

AC:

683

AN:

22828

American (AMR)

AF:

0.00145

AC:

AN:

8284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14208

East Asian (EAS)

AF:

0.00

AC:

AN:

26520

South Asian (SAS)

AF:

0.00

AC:

AN:

20164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35600

Middle Eastern (MID)

AF:

0.00407

AC:

AN:

3436

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

928870

Other (OTH)

AF:

0.00277

AC:

122

AN:

44010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00844

AC:

1278

AN:

151448

Hom.:

Cov.:

AF XY:

0.00837

AC XY:

619

AN XY:

73980

show subpopulations

African (AFR)

AF:

0.0296

AC:

1225

AN:

41412

American (AMR)

AF:

0.00216

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10478

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67632

Other (OTH)

AF:

0.00428

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

176

235

294

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00439

Hom.:

Bravo

AF:

0.00949

ESP6500AA

AF:

0.0296

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00374

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.093

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0056

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.81

PhyloP100

0.56

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.23

REVEL

Uncertain

0.50

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

0.80

Vest4

0.35

MVP

0.72

MPC

1.4

ClinPred

0.044

GERP RS

2.1

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.10

gMVP

0.33

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over