1-170664360-A-C

Position:

• chr1-170664360-A-C

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>C​(p.Met48Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., 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=0.2035169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRRX1	NM_022716.4	c.142A>C	p.Met48Leu	missense_variant	1/4	ENST00000239461.11	NP_073207.1
PRRX1	NM_006902.5	c.142A>C	p.Met48Leu	missense_variant	1/5		NP_008833.1
PRRX1	XM_006711388.4	c.1A>C	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>C	p.Met48Leu	missense_variant	1/4	1	NM_022716.4	ENSP00000239461.6
PRRX1	ENST00000367760.7	c.142A>C	p.Met48Leu	missense_variant	1/5	1		ENSP00000356734.3
PRRX1	ENST00000497230.2	c.142A>C	p.Met48Leu	missense_variant	1/3	2		ENSP00000450762.1
PRRX1	ENST00000553786.1	n.252A>C		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 28, 2024

Variant summary: PRRX1 c.142A>C (p.Met48Leu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249812 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.142A>C in individuals affected with Agnathia-Otocephaly Complex and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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	0.93	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

LitVar

Other links and lift over

dbSNP: rs945516523; hg19: chr1-170633501;