rs368123079

Variant names:

• chr20-21709456-A-C
• rs368123079
• NM_001257096.2:c.1282+12A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001257096.2(PAX1):​c.1282+12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,509,864 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (21 hom.)
• Consequence: PAX1 NM_001257096.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -3.28
• Publications: 0 publications found

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]

PAX1 Gene-Disease associations (from GenCC):

• otofaciocervical syndrome 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 20-21709456-A-C is Benign according to our data. Variant chr20-21709456-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445455.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00313 (477/152272) while in subpopulation NFE AF = 0.00559 (380/68006). AF 95% confidence interval is 0.00512. There are 1 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257096.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX1	NM_001257096.2	MANE Select	c.1282+12A>C		intron	N/A	NP_001244025.1	A0A087WXV5
	PAX1	NM_006192.5		c.1282+12A>C		intron	N/A	NP_006183.2	P15863-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX1	ENST00000613128.5	TSL:1 MANE Select	c.1282+12A>C		intron	N/A	ENSP00000481334.1	A0A087WXV5
	PAX1	ENST00000398485.6	TSL:5	c.1282+12A>C		intron	N/A	ENSP00000381499.2	P15863-1
	PAX1	ENST00000444366.2	TSL:2	c.1210+12A>C		intron	N/A	ENSP00000410355.2	P15863-2

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 477 AN: 152154 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00261 AC: 308 AN: 118064 AF XY: 0.00253

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000167

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000862

Gnomad NFE exome AF: 0.00574

Gnomad OTH exome AF: 0.00222

GnomAD4 exome AF: 0.00521 AC: 7068 AN: 1357592 Hom.: 21 Cov.: 30 AF XY: 0.00511 AC XY: 3417 AN XY: 668084

African (AFR) AF: 0.000848 AC: 26 AN: 30674

American (AMR) AF: 0.00111 AC: 36 AN: 32362

Ashkenazi Jewish (ASJ) AF: 0.0000860 AC: 2 AN: 23246

East Asian (EAS) AF: 0.00 AC: 0 AN: 35470

South Asian (SAS) AF: 0.000186 AC: 14 AN: 75442

European-Finnish (FIN) AF: 0.00159 AC: 56 AN: 35268

Middle Eastern (MID) AF: 0.000502 AC: 2 AN: 3986

European-Non Finnish (NFE) AF: 0.00631 AC: 6720 AN: 1064642

Other (OTH) AF: 0.00375 AC: 212 AN: 56502

GnomAD4 genome AF: 0.00313 AC: 477 AN: 152272 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74452

African (AFR) AF: 0.00120 AC: 50 AN: 41570

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00559 AC: 380 AN: 68006

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00288

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.025
DANN	Benign	0.59
PhyloP100		-3.3
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs368123079; hg19: chr20-21690094;