chr20-21705774-C-G

Variant names:

• chr20-21705774-C-G
• rs2122130378
• NM_001257096.2:c.62C>G

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.62C>G​(p.Ala21Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Synonymous variant affecting the same amino acid position (i.e. A21A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX1 NM_001257096.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.345

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=0.20202386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.62C>G	p.Ala21Gly	missense_variant	Exon 1 of 5	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.62C>G	p.Ala21Gly	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.62C>G	p.Ala21Gly	missense_variant	Exon 1 of 5	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.62C>G	p.Ala21Gly	missense_variant	Exon 1 of 5	5		ENSP00000381499.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1109774 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 529392

African (AFR) AF: 0.00 AC: 0 AN: 22872

American (AMR) AF: 0.00 AC: 0 AN: 8352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14176

East Asian (EAS) AF: 0.00 AC: 0 AN: 26680

South Asian (SAS) AF: 0.00 AC: 0 AN: 20594

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3096

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 934802

Other (OTH) AF: 0.00 AC: 0 AN: 44268

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 08, 2023

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 glycine, which is neutral and non-polar, at codon 21 of the PAX1 protein (p.Ala21Gly). 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: 1386395). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. 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	0.079
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.48	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	0.057	D
MutationAssessor	Benign	0.81	L;.
PhyloP100		0.34
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.15	N;.
REVEL	Benign	0.24
Sift	Uncertain	0.011	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0020	B;.
Vest4		0.26
MutPred		0.31		Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);
MVP		0.71
MPC		1.3
ClinPred		0.14	T
GERP RS		1.8
PromoterAI		-0.042	Neutral
Varity_R		0.058
gMVP		0.17
Mutation Taster		=95/5	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

LitVar

Other links and lift over

dbSNP: rs2122130378; hg19: chr20-21686412;