chr20-21705764-G-A

Variant names:

• chr20-21705764-G-A
• rs1347724154
• NM_001257096.2:c.52G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001257096.2(PAX1):​c.52G>A​(p.Gly18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000027 in 1,110,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PAX1 NM_001257096.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050703913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.52G>A	p.Gly18Arg	missense_variant	Exon 1 of 5	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.52G>A	p.Gly18Arg	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.52G>A	p.Gly18Arg	missense_variant	Exon 1 of 5	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.52G>A	p.Gly18Arg	missense_variant	Exon 1 of 5	5		ENSP00000381499.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000270 AC: 3 AN: 1110958 Hom.: 0 Cov.: 31 AF XY: 0.00000189 AC XY: 1 AN XY: 529474

African (AFR) AF: 0.00 AC: 0 AN: 22920

American (AMR) AF: 0.00 AC: 0 AN: 8388

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14266

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 20598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3204

European-Non Finnish (NFE) AF: 0.00000321 AC: 3 AN: 934966

Other (OTH) AF: 0.00 AC: 0 AN: 44386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.0
DANN	Benign	0.92
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.44	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.051	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	-0.81	N;.
PhyloP100		0.0060
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.67	N;.
REVEL	Benign	0.21
Sift	Benign	0.44	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.29		Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);
MVP		0.38
MPC		1.6
ClinPred		0.067	T
GERP RS		-0.29
PromoterAI		0.071	Neutral
Varity_R		0.067
gMVP		0.11
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: rs1347724154; hg19: chr20-21686402; COSMIC: COSV68273448; COSMIC: COSV68273448;