1-170664360-A-T

Position:

• chr1-170664360-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022716.4(PRRX1):​c.142A>T​(p.Met48Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M48I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRRX1 NM_022716.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20440575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRX1	NM_022716.4	c.142A>T	p.Met48Leu	missense_variant	1/4	ENST00000239461.11	NP_073207.1
PRRX1	NM_006902.5	c.142A>T	p.Met48Leu	missense_variant	1/5		NP_008833.1
PRRX1	XM_006711388.4	c.1A>T	p.Met1?	initiator_codon_variant	2/5		XP_006711451.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRRX1	ENST00000239461.11	c.142A>T	p.Met48Leu	missense_variant	1/4	1	NM_022716.4	ENSP00000239461.6
PRRX1	ENST00000367760.7	c.142A>T	p.Met48Leu	missense_variant	1/5	1		ENSP00000356734.3
PRRX1	ENST00000497230.2	c.142A>T	p.Met48Leu	missense_variant	1/3	2		ENSP00000450762.1
PRRX1	ENST00000553786.1	n.252A>T		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.142A>T (p.M48L) alteration is located in exon 1 (coding exon 1) of the PRRX1 gene. This alteration results from a A to T substitution at nucleotide position 142, causing the methionine (M) at amino acid position 48 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.16	.;T;T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.49	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.10	B;B;.
Vest4		0.45
MutPred		0.31		Gain of disorder (P = 0.2786);Gain of disorder (P = 0.2786);Gain of disorder (P = 0.2786);
MVP		0.82
MPC		1.0
ClinPred		0.86	D
GERP RS		3.5
Varity_R		0.36
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-170633501;