NM_022716.4:c.338T>C

Variant names:

• chr1-170719822-T-C
• rs387906667
• NM_022716.4:c.338T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_022716.4(PRRX1):​c.338T>C​(p.Phe113Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRRX1 NM_022716.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 2 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: AR, Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• multiple congenital anomalies/dysmorphic syndrome-intellectual disability

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-170719822-T-C is Pathogenic according to our data. Variant chr1-170719822-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 29825.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022716.4. 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
	PRRX1	NM_022716.4	MANE Select	c.338T>C	p.Phe113Ser	missense	Exon 2 of 4	NP_073207.1	P54821-1
	PRRX1	NM_006902.5		c.338T>C	p.Phe113Ser	missense	Exon 2 of 5	NP_008833.1	P54821-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRRX1	ENST00000239461.11	TSL:1 MANE Select	c.338T>C	p.Phe113Ser	missense	Exon 2 of 4	ENSP00000239461.6	P54821-1
	PRRX1	ENST00000367760.7	TSL:1	c.338T>C	p.Phe113Ser	missense	Exon 2 of 5	ENSP00000356734.3	P54821-2
	PRRX1	ENST00000497230.2	TSL:2	c.338T>C	p.Phe113Ser	missense	Exon 2 of 3	ENSP00000450762.1	G3V2N3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Agnathia-otocephaly complex (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.2	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.99
MutPred		0.86		Gain of phosphorylation at F113 (P = 0.0128)
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.92
Mutation Taster		=0/100	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: rs387906667; hg19: chr1-170688963;