chr1-213996654-C-T

Variant names:

• chr1-213996654-C-T
• rs753030931
• NM_001270616.2:c.119C>T

Variant summary

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

The NM_001270616.2(PROX1):​c.119C>T​(p.Thr40Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T40R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.31
• 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.119C>T	p.Thr40Met	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.119C>T	p.Thr40Met	missense_variant	Exon 2 of 5	1	NM_001270616.2	ENSP00000355925.4
PROX1	ENST00000435016.2	c.119C>T	p.Thr40Met	missense_variant	Exon 2 of 5	1		ENSP00000400694.1
PROX1	ENST00000471129.1	c.119C>T	p.Thr40Met	missense_variant	Exon 2 of 2	3		ENSP00000419517.1
PROX1	ENST00000607425.1	c.119C>T	p.Thr40Met	missense_variant	Exon 2 of 2	3		ENSP00000475357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T;T;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.55	.;N;N;N;N;.
PhyloP100		7.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.0	N;N;N;N;N;.
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D;D;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		0.98	.;D;D;D;D;.
Vest4		0.44, 0.44, 0.44
MutPred		0.61		Loss of phosphorylation at T40 (P = 0.029);Loss of phosphorylation at T40 (P = 0.029);Loss of phosphorylation at T40 (P = 0.029);Loss of phosphorylation at T40 (P = 0.029);Loss of phosphorylation at T40 (P = 0.029);Loss of phosphorylation at T40 (P = 0.029);
MVP		0.43
MPC		1.5
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.49
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753030931; hg19: chr1-214169997;