chr1-170724773-T-C

Variant names:

• chr1-170724773-T-C
• rs2421491
• NM_022716.4:c.418-1447T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022716.4(PRRX1):​c.418-1447T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 152,182 control chromosomes in the GnomAD database, including 4,392 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (4392 hom., cov: 32)
• Consequence: PRRX1 NM_022716.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.634
• Publications: 5 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

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.418-1447T>C		intron	N/A	NP_073207.1	P54821-1
	PRRX1	NM_006902.5		c.418-1447T>C		intron	N/A	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.418-1447T>C		intron	N/A	ENSP00000239461.6	P54821-1
	PRRX1	ENST00000367760.7	TSL:1	c.418-1447T>C		intron	N/A	ENSP00000356734.3	P54821-2
	PRRX1	ENST00000497230.2	TSL:2	c.418-1447T>C		intron	N/A	ENSP00000450762.1	G3V2N3

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32566 AN: 152064 Hom.: 4389 Cov.: 32

Gnomad AFR AF: 0.0635

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.256

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.214 AC: 32576 AN: 152182 Hom.: 4392 Cov.: 32 AF XY: 0.220 AC XY: 16331 AN XY: 74400

African (AFR) AF: 0.0634 AC: 2635 AN: 41560

American (AMR) AF: 0.325 AC: 4973 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1298 AN: 3470

East Asian (EAS) AF: 0.122 AC: 630 AN: 5184

South Asian (SAS) AF: 0.268 AC: 1294 AN: 4824

European-Finnish (FIN) AF: 0.289 AC: 3048 AN: 10556

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17852 AN: 67980

Other (OTH) AF: 0.253 AC: 534 AN: 2114

Alfa AF: 0.225 Hom.: 591

Bravo AF: 0.210

Asia WGS AF: 0.178 AC: 621 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.98
DANN	Benign	0.20
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism (auto)

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: rs2421491; hg19: chr1-170693914;