1-214035670-G-A

Variant names:

• chr1-214035670-G-A
• rs1348973727
• NM_001270616.2:c.2050G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001270616.2(PROX1):​c.2050G>A​(p.Val684Ile) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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]

LINC02775 (HGNC:54294): (long intergenic non-protein coding RNA 2775)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39430133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROX1	NM_001270616.2	c.2050G>A	p.Val684Ile	missense_variant	Exon 5 of 5	ENST00000366958.9	NP_001257545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROX1	ENST00000366958.9	c.2050G>A	p.Val684Ile	missense_variant	Exon 5 of 5	1	NM_001270616.2	ENSP00000355925.4
PROX1	ENST00000435016.2	c.2050G>A	p.Val684Ile	missense_variant	Exon 5 of 5	1		ENSP00000400694.1
LINC02775	ENST00000729802.1	n.281-13230C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2050G>A (p.V684I) alteration is located in exon 5 (coding exon 4) of the PROX1 gene. This alteration results from a G to A substitution at nucleotide position 2050, causing the valine (V) at amino acid position 684 to be replaced by an isoleucine (I). 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	Uncertain	0.48
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;.;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	L;L;L;L
PhyloP100		10
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.30	N;.;N;N
REVEL	Benign	0.28
Sift	Benign	0.62	T;.;T;T
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.12	B;B;B;B
Vest4		0.58
MutPred		0.66		Gain of catalytic residue at L689 (P = 0.0649);Gain of catalytic residue at L689 (P = 0.0649);Gain of catalytic residue at L689 (P = 0.0649);Gain of catalytic residue at L689 (P = 0.0649);
MVP		0.83
MPC		1.3
ClinPred		0.65	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.58
Mutation Taster		=57/43	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

dbSNP: rs1348973727; hg19: chr1-214209013;