rs398122375

Variant names:

• chr1-170719746-GA-G
• rs398122375
• NM_022716.4:c.269delA

Your query was ambiguous. Multiple possible variants found:

• chr1-170719746-GA-G
• chr1-170719746-GA-GAAAAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_022716.4(PRRX1):​c.269delA​(p.Lys90ArgfsTer42) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRRX1 NM_022716.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.43
• Publications: 0 publications found

Genes affected

PRRX1 (HGNC:9142): (paired related homeobox 1) The DNA-associated protein encoded by this gene is a member of the paired family of homeobox proteins localized to the nucleus. The protein functions as a transcription co-activator, enhancing the DNA-binding activity of serum response factor, a protein required for the induction of genes by growth and differentiation factors. The protein regulates muscle creatine kinase, indicating a role in the establishment of diverse mesodermal muscle types. Alternative splicing yields two isoforms that differ in abundance and expression patterns. [provided by RefSeq, Jul 2008]

PRRX1 Gene-Disease associations (from GenCC):

• craniosynostosis

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• agnathia-otocephaly complex

  Inheritance: AD, Unknown, AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• multiple congenital anomalies/dysmorphic syndrome-intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-170719746-GA-G is Pathogenic according to our data. Variant chr1-170719746-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 50496.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRRX1	NM_022716.4	c.269delA	p.Lys90ArgfsTer42	frameshift_variant	Exon 2 of 4	ENST00000239461.11	NP_073207.1
PRRX1	NM_006902.5	c.269delA	p.Lys90ArgfsTer42	frameshift_variant	Exon 2 of 5		NP_008833.1
PRRX1	XM_006711388.4	c.128delA	p.Lys43ArgfsTer42	frameshift_variant	Exon 3 of 5		XP_006711451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRRX1	ENST00000239461.11	c.269delA	p.Lys90ArgfsTer42	frameshift_variant	Exon 2 of 4	1	NM_022716.4	ENSP00000239461.6
PRRX1	ENST00000367760.7	c.269delA	p.Lys90ArgfsTer42	frameshift_variant	Exon 2 of 5	1		ENSP00000356734.3
PRRX1	ENST00000497230.2	c.269delA	p.Lys90ArgfsTer42	frameshift_variant	Exon 2 of 3	2		ENSP00000450762.1
PRRX1	ENST00000553786.1	n.379delA		non_coding_transcript_exon_variant	Exon 3 of 3	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Agnathia-otocephaly complex Pathogenic:1

Sep 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=4/196	disease causing (ClinVar)

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: rs398122375; hg19: chr1-170688887; COSMIC: COSV53420459; COSMIC: COSV53420459;