chr1-213996948-C-A

Position:

• chr1-213996948-C-A

Variant summary

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

The NM_001270616.2(PROX1):​c.413C>A​(p.Pro138Gln) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

Genes affected

PROX1 (HGNC:9459): (prospero homeobox 1) The protein encoded by this gene is a member of the homeobox transcription factor family. Members of this family contain a homeobox domain that consists of a 60-amino acid helix-turn-helix structure that binds DNA and RNA. The protein encoded by this gene is conserved across vertebrates and may play an essential role during development. Altered levels of this protein have been reported in cancers of different organs, such as colon, brain, blood, breast, pancreas, liver and esophagus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

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=0.13713759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROX1	NM_001270616.2	c.413C>A	p.Pro138Gln	missense_variant	2/5	ENST00000366958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROX1	ENST00000366958.9	c.413C>A	p.Pro138Gln	missense_variant	2/5	1	NM_001270616.2	P1
PROX1	ENST00000435016.2	c.413C>A	p.Pro138Gln	missense_variant	2/5	1		P1
PROX1	ENST00000471129.1	c.413C>A	p.Pro138Gln	missense_variant	2/2	3
PROX1	ENST00000607425.1	c.413C>A	p.Pro138Gln	missense_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Ambry Genetics

Mar 30, 2024

The c.413C>A (p.P138Q) alteration is located in exon 2 (coding exon 1) of the PROX1 gene. This alteration results from a C to A substitution at nucleotide position 413, causing the proline (P) at amino acid position 138 to be replaced by a glutamine (Q). 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	0.047
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.11	.;T;T;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	D;.;.;D;.;D
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.14	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;N;N;N;N;.
MutationTaster	Benign	0.82	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.2	N;N;N;N;N;.
REVEL	Benign	0.066
Sift	Benign	0.91	T;T;T;T;T;.
Sift4G	Benign	0.41	T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;B;.
Vest4		0.21, 0.21, 0.20, 0.21
MutPred		0.33		Loss of catalytic residue at P137 (P = 0.0121);Loss of catalytic residue at P137 (P = 0.0121);Loss of catalytic residue at P137 (P = 0.0121);Loss of catalytic residue at P137 (P = 0.0121);Loss of catalytic residue at P137 (P = 0.0121);Loss of catalytic residue at P137 (P = 0.0121);
MVP		0.24
MPC		0.60
ClinPred		0.77	D
GERP RS		5.6
Varity_R		0.14
gMVP		0.12

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: rs867494593; hg19: chr1-214170291;