1-213996711-T-G

Variant names:

• chr1-213996711-T-G
• rs375594682
• NM_001270616.2:c.176T>G

Variant summary

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

The NM_001270616.2(PROX1):​c.176T>G​(p.Val59Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V59A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• 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.176T>G	p.Val59Gly	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.176T>G	p.Val59Gly	missense_variant	Exon 2 of 5	1	NM_001270616.2	ENSP00000355925.4
PROX1	ENST00000435016.2	c.176T>G	p.Val59Gly	missense_variant	Exon 2 of 5	1		ENSP00000400694.1
PROX1	ENST00000471129.1	c.176T>G	p.Val59Gly	missense_variant	Exon 2 of 2	3		ENSP00000419517.1
PROX1	ENST00000607425.1	c.176T>G	p.Val59Gly	missense_variant	Exon 2 of 2	3		ENSP00000475357.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251474 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;T;T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;.;.;T;.;T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.0	.;L;L;L;L;.
PhyloP100		5.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.2	N;N;N;N;N;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;T;T;T;T;D
Polyphen		1.0	.;D;D;D;D;.
Vest4		0.75, 0.75, 0.75
MutPred		0.67		Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);Loss of sheet (P = 0.0025);
MVP		0.83
MPC		1.9
ClinPred		0.64	D
GERP RS		5.8
Varity_R		0.47
gMVP		0.41
Mutation Taster		=41/59	disease causing

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: rs375594682; hg19: chr1-214170054;