rs368123079

Positions:

• chr20-21709456-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.28

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 Benign. Variant got -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 id is 445455.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.1282+12A>C		intron_variant		ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.1282+12A>C		intron_variant			NP_006183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX1	ENST00000613128.5	c.1282+12A>C		intron_variant		1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.1282+12A>C		intron_variant		5		ENSP00000381499.2
PAX1	ENST00000444366.2	c.1210+12A>C		intron_variant		2		ENSP00000410355.2

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 477 AN: 152154 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00261 AC: 308 AN: 118064 Hom.: 0 AF XY: 0.00253 AC XY: 161 AN XY: 63684

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 SAS exome AF: 0.000109

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.: 21 Cov.: 30 AF XY: 0.00511 AC XY: 3417 AN XY: 668084

Gnomad4 AFR exome AF: 0.000848

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.0000860

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00159

Gnomad4 NFE exome AF: 0.00631

Gnomad4 OTH exome AF: 0.00375

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74452

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00559

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00275 Hom.: 0

Bravo AF: 0.00288

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PAX1: BS1 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 30, 2022

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
DANN	Benign	0.59

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

LitVar

Other links and lift over

dbSNP: rs368123079; hg19: chr20-21690094;