chr1-170664403-G-A

Position:

• chr1-170664403-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022716.4(PRRX1):​c.185G>A​(p.Arg62Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,611,706 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (57 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (38 hom.)
• Consequence: PRRX1 NM_022716.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.78

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042603016).
• BP6: Variant 1-170664403-G-A is Benign according to our data. Variant chr1-170664403-G-A is described in ClinVar as [Benign]. Clinvar id is 725559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (2000/152292) while in subpopulation AFR AF= 0.0446 (1855/41550). AF 95% confidence interval is 0.043. There are 57 homozygotes in gnomad4. There are 926 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 57 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRX1	NM_022716.4	c.185G>A	p.Arg62Gln	missense_variant	1/4	ENST00000239461.11	NP_073207.1
PRRX1	NM_006902.5	c.185G>A	p.Arg62Gln	missense_variant	1/5		NP_008833.1
PRRX1	XM_006711388.4	c.44G>A	p.Arg15Gln	missense_variant	2/5		XP_006711451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRX1	ENST00000239461.11	c.185G>A	p.Arg62Gln	missense_variant	1/4	1	NM_022716.4	ENSP00000239461.6
PRRX1	ENST00000367760.7	c.185G>A	p.Arg62Gln	missense_variant	1/5	1		ENSP00000356734.3
PRRX1	ENST00000497230.2	c.185G>A	p.Arg62Gln	missense_variant	1/3	2		ENSP00000450762.1
PRRX1	ENST00000553786.1	n.295G>A		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1998 AN: 152176 Hom.: 57 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00346 AC: 838 AN: 242518 Hom.: 18 AF XY: 0.00254 AC XY: 335 AN XY: 131966

Gnomad AFR exome AF: 0.0453

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00284

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000668

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00203

GnomAD4 exome AF: 0.00140 AC: 2041 AN: 1459414 Hom.: 38 Cov.: 33 AF XY: 0.00120 AC XY: 869 AN XY: 725846

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00272

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000933

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.00297

GnomAD4 genome AF: 0.0131 AC: 2000 AN: 152292 Hom.: 57 Cov.: 32 AF XY: 0.0124 AC XY: 926 AN XY: 74466

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.00640

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.0744 Hom.: 2357

Bravo AF: 0.0146

ESP6500AA AF: 0.0370 AC: 163

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00408 AC: 495

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	.;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Uncertain	-0.077	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.32	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.59	T;T;T
Polyphen		0.98	D;D;.
Vest4		0.36
MVP		0.82
MPC		1.2
ClinPred		0.082	T
GERP RS		4.6
Varity_R		0.30
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs74674242; hg19: chr1-170633544; COSMIC: COSV99057059; COSMIC: COSV99057059;