1-213997208-G-C

Variant names:

• chr1-213997208-G-C
• NM_001270616.2:c.673G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001270616.2(PROX1):​c.673G>C​(p.Val225Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 6.76
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROX1	NM_001270616.2	c.673G>C	p.Val225Leu	missense_variant	Exon 2 of 5	ENST00000366958.9	NP_001257545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROX1	ENST00000366958.9	c.673G>C	p.Val225Leu	missense_variant	Exon 2 of 5	1	NM_001270616.2	ENSP00000355925.4
PROX1	ENST00000435016.2	c.673G>C	p.Val225Leu	missense_variant	Exon 2 of 5	1		ENSP00000400694.1
PROX1	ENST00000471129.1	c.673G>C	p.Val225Leu	missense_variant	Exon 2 of 2	3		ENSP00000419517.1
PROX1	ENST00000607425.1	c.*244G>C		downstream_gene_variant		3		ENSP00000475357.1

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

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673G>C (p.V225L) alteration is located in exon 2 (coding exon 1) of the PROX1 gene. This alteration results from a G to C substitution at nucleotide position 673, causing the valine (V) at amino acid position 225 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	0.22
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;.;.;D;.
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	.;L;L;L;L
PhyloP100		6.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.1	N;N;N;N;N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;T;T;T;T
Sift4G	Uncertain	0.031	D;T;T;T;T
Polyphen		0.97	.;D;D;D;D
Vest4		0.61, 0.61, 0.61, 0.60
MutPred		0.58		Loss of methylation at K229 (P = 0.0867);Loss of methylation at K229 (P = 0.0867);Loss of methylation at K229 (P = 0.0867);Loss of methylation at K229 (P = 0.0867);Loss of methylation at K229 (P = 0.0867);
MVP		0.43
MPC		1.6
ClinPred		0.83	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.36
Mutation Taster		=63/37	polymorphism

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

hg19: chr1-214170551;