20-21705767-G-A

Variant names:

• chr20-21705767-G-A
• rs2122130353
• NM_001257096.2:c.55G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001257096.2(PAX1):​c.55G>A​(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000018 in 1,111,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: PAX1 NM_001257096.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24084815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 5	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 5		NP_006183.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX1	ENST00000613128.5	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 5	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 5	5		ENSP00000381499.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000180 AC: 2 AN: 1111670 Hom.: 0 Cov.: 31 AF XY: 0.00000189 AC XY: 1 AN XY: 530244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22918

American (AMR) AF: 0.00 AC: 0 AN: 8374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14244

East Asian (EAS) AF: 0.00 AC: 0 AN: 26778

South Asian (SAS) AF: 0.0000484 AC: 1 AN: 20662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3164

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 935788

Other (OTH) AF: 0.00 AC: 0 AN: 44414

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 19 of the PAX1 protein (p.Ala19Thr). 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: 1495567). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.40	T;T
M_CAP	Pathogenic	0.91	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Benign	0.90	L;.
PhyloP100		1.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.29	N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.26	T;T
Polyphen		0.0020	B;.
Vest4		0.33
MutPred		0.27		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.72
MPC		1.3
ClinPred		0.077	T
GERP RS		-1.6
PromoterAI		0.097	Neutral
Varity_R		0.071
gMVP		0.30
Mutation Taster		=97/3	polymorphism

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

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Other links and lift over

dbSNP: rs2122130353; hg19: chr20-21686405;