rs138641387

chr20-21714718-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001257096.2(PAX1):c.*156C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,605,734 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (35 hom.)
• Consequence: PAX1 NM_001257096.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.158

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00380221).
• BP6: Variant 20-21714718-C-T is Benign according to our data. Variant chr20-21714718-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 377263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.003 (457/152280) while in subpopulation SAS AF= 0.0176 (85/4822). AF 95% confidence interval is 0.0146. There are 1 homozygotes in gnomad4. There are 255 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX1	NM_001257096.2	c.*156C>T		3_prime_UTR_variant	5/5	ENST00000613128.5
PAX1	NM_006192.5	c.1520C>T	p.Pro507Leu	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX1	ENST00000613128.5	c.*156C>T		3_prime_UTR_variant	5/5	1	NM_001257096.2	P1
PAX1	ENST00000398485.6	c.1520C>T	p.Pro507Leu	missense_variant	5/5	5
PAX1	ENST00000444366.2	c.*156C>T		3_prime_UTR_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0176

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00472 AC: 1137 AN: 240786 Hom.: 10 AF XY: 0.00553 AC XY: 726 AN XY: 131236

Gnomad AFR exome AF: 0.00128

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00411

Gnomad EAS exome AF: 0.000166

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.00311

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00501

GnomAD4 exome AF: 0.00386 AC: 5612 AN: 1453454 Hom.: 35 Cov.: 31 AF XY: 0.00432 AC XY: 3123 AN XY: 723488

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0163

Gnomad4 FIN exome AF: 0.00326

Gnomad4 NFE exome AF: 0.00315

Gnomad4 OTH exome AF: 0.00453

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00343 AC XY: 255 AN XY: 74452

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00360 Hom.: 2

Bravo AF: 0.00241

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00505 AC: 608

Asia WGS AF: 0.00606 AC: 22 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

PAX1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	5.9
Dann	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0038	T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.022	D
Polyphen		0.0	B
Vest4		0.13
MVP		0.10
MPC		0.24
ClinPred		0.040	T
GERP RS		-2.1
Varity_R		0.042
gMVP		0.11

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: rs138641387; hg19: chr20-21695356;