rs1555804780

chr20-21709329-G-GGGCCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001257096.2(PAX1):c.1169_1173dup(p.Pro392AlafsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX1 NM_001257096.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.34

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

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-21709329-G-GGGCCC is Pathogenic according to our data. Variant chr20-21709329-G-GGGCCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522604.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX1	NM_001257096.2	c.1169_1173dup	p.Pro392AlafsTer19	frameshift_variant	4/5	ENST00000613128.5
PAX1	NM_006192.5	c.1169_1173dup	p.Pro392AlafsTer19	frameshift_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX1	ENST00000613128.5	c.1169_1173dup	p.Pro392AlafsTer19	frameshift_variant	4/5	1	NM_001257096.2	P1
PAX1	ENST00000398485.6	c.1169_1173dup	p.Pro392AlafsTer19	frameshift_variant	4/5	5
PAX1	ENST00000444366.2	c.1097_1101dup	p.Pro368AlafsTer19	frameshift_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Otofaciocervical syndrome 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	Jan 01, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 26, 2019	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555804780; hg19: chr20-21689967;