20-21705759-G-A

Variant names:

• chr20-21705759-G-A
• rs1359631755
• NM_001257096.2:c.47G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001257096.2(PAX1):​c.47G>A​(p.Trp16*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,262,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: PAX1 NM_001257096.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.54

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PP5: Variant 20-21705759-G-A is Pathogenic according to our data. Variant chr20-21705759-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1460324.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.47G>A	p.Trp16*	stop_gained	Exon 1 of 5	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.47G>A	p.Trp16*	stop_gained	Exon 1 of 5		NP_006183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX1	ENST00000613128.5	c.47G>A	p.Trp16*	stop_gained	Exon 1 of 5	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.47G>A	p.Trp16*	stop_gained	Exon 1 of 5	5		ENSP00000381499.2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151360 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000153 AC: 17 AN: 1111582 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 8 AN XY: 529790

African (AFR) AF: 0.00 AC: 0 AN: 22938

American (AMR) AF: 0.00 AC: 0 AN: 8396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14288

East Asian (EAS) AF: 0.00 AC: 0 AN: 26808

South Asian (SAS) AF: 0.00 AC: 0 AN: 20582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3306

European-Non Finnish (NFE) AF: 0.0000171 AC: 16 AN: 935276

Other (OTH) AF: 0.0000225 AC: 1 AN: 44408

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151360 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73854

African (AFR) AF: 0.0000484 AC: 2 AN: 41348

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67642

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp16*) in the PAX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX1 are known to be pathogenic (PMID: 1889089, 23851939, 28657137, 29681087). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PAX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1460324). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	43
DANN	Uncertain	0.99
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		2.5
Vest4		0.63
GERP RS		4.5
PromoterAI		0.013	Neutral
Mutation Taster		=22/178	disease causing (fs/PTC)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs1359631755; hg19: chr20-21686397;