20-21705735-G-C

Variant names:

• chr20-21705735-G-C
• rs1984954100
• NM_001257096.2:c.23G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001257096.2(PAX1):​c.23G>C​(p.Gly8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G8E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: PAX1 NM_001257096.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29824698).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX1	NM_001257096.2	c.23G>C	p.Gly8Ala	missense_variant	Exon 1 of 5	ENST00000613128.5	NP_001244025.1
PAX1	NM_006192.5	c.23G>C	p.Gly8Ala	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.23G>C	p.Gly8Ala	missense_variant	Exon 1 of 5	1	NM_001257096.2	ENSP00000481334.1
PAX1	ENST00000398485.6	c.23G>C	p.Gly8Ala	missense_variant	Exon 1 of 5	5		ENSP00000381499.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097606 Hom.: 0 Cov.: 31 AF XY: 0.00000192 AC XY: 1 AN XY: 520366

African (AFR) AF: 0.00 AC: 0 AN: 22810

American (AMR) AF: 0.00 AC: 0 AN: 8240

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 26474

South Asian (SAS) AF: 0.00 AC: 0 AN: 19726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3520

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 923484

Other (OTH) AF: 0.00 AC: 0 AN: 43700

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.048
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.59	T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	0.97	L;.
PhyloP100		1.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.36	N;.
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.48	P;.
Vest4		0.11
MutPred		0.39		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.52
MPC		2.6
ClinPred		0.66	D
GERP RS		3.4
PromoterAI		0.16	Neutral
Varity_R		0.21
gMVP		0.29
Mutation Taster		=92/8	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: rs1984954100; hg19: chr20-21686373;