20-21706648-G-T

Position:

• chr20-21706648-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001257096.2(PAX1):​c.497G>T​(p.Gly166Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PAX1 NM_001257096.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.74

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 20-21706648-G-T is Pathogenic according to our data. Variant chr20-21706648-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 89026.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.497G>T	p.Gly166Val	missense_variant	2/5	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.497G>T	p.Gly166Val	missense_variant	2/5		NP_006183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX1	ENST00000613128.5	c.497G>T	p.Gly166Val	missense_variant	2/5	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.497G>T	p.Gly166Val	missense_variant	2/5	5		ENSP00000381499.2
PAX1	ENST00000444366.2	c.425G>T	p.Gly142Val	missense_variant	1/4	2		ENSP00000410355.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249290 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459912 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726390

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PAX1 function (PMID: 23851939). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 89026). This missense change has been observed in individual(s) with otofaciocervical syndrome (PMID: 23851939). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs540296842, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 166 of the PAX1 protein (p.Gly166Val). -

Otofaciocervical syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-9.0	D;.;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.81		Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.87

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: rs540296842; hg19: chr20-21687286;