1-213996953-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001270616.2(PROX1):c.418T>C(p.Cys140Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PROX1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROX1	NM_001270616.2	c.418T>C	p.Cys140Arg	missense_variant	2/5	ENST00000366958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROX1	ENST00000366958.9	c.418T>C	p.Cys140Arg	missense_variant	2/5	1	NM_001270616.2	P1
PROX1	ENST00000435016.2	c.418T>C	p.Cys140Arg	missense_variant	2/5	1		P1
PROX1	ENST00000471129.1	c.418T>C	p.Cys140Arg	missense_variant	2/2	3
PROX1	ENST00000607425.1	c.418T>C	p.Cys140Arg	missense_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

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

Jan 18, 2023

The c.418T>C (p.C140R) alteration is located in exon 2 (coding exon 1) of the PROX1 gene. This alteration results from a T to C substitution at nucleotide position 418, causing the cysteine (C) at amino acid position 140 to be replaced by an arginine (R). 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	0.24
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;.;.;D;.;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N;N;N;N;N;.
REVEL	Benign	0.28
Sift	Benign	0.14	T;T;D;T;T;.
Sift4G	Pathogenic	0.0	D;T;T;T;T;D
Polyphen		1.0	.;D;D;D;D;.
Vest4		0.82, 0.82, 0.82, 0.82
MutPred		0.48		Loss of catalytic residue at L141 (P = 0.0334);Loss of catalytic residue at L141 (P = 0.0334);Loss of catalytic residue at L141 (P = 0.0334);Loss of catalytic residue at L141 (P = 0.0334);Loss of catalytic residue at L141 (P = 0.0334);Loss of catalytic residue at L141 (P = 0.0334);
MVP		0.55
MPC		2.2
ClinPred		0.92	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.53

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: chr1-214170296;