chr1-214004636-T-C

Variant names:

• chr1-214004636-T-C
• rs2289002
• NM_001270616.2:c.1726-529T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001270616.2(PROX1):​c.1726-529T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,072 control chromosomes in the GnomAD database, including 6,743 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (6743 hom., cov: 33)
• Consequence: PROX1 NM_001270616.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.221
• Publications: 2 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]

PROX1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.398 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270616.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX1	NM_001270616.2	MANE Select	c.1726-529T>C		intron	N/A	NP_001257545.1	Q92786
	PROX1	NM_002763.5		c.1726-529T>C		intron	N/A	NP_002754.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX1	ENST00000366958.9	TSL:1 MANE Select	c.1726-529T>C		intron	N/A	ENSP00000355925.4	Q92786
	PROX1	ENST00000435016.2	TSL:1	c.1726-529T>C		intron	N/A	ENSP00000400694.1	Q92786
	PROX1	ENST00000881021.1		c.1726-529T>C		intron	N/A	ENSP00000551080.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44527 AN: 151954 Hom.: 6730 Cov.: 33

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.313

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.301

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.293 AC: 44590 AN: 152072 Hom.: 6743 Cov.: 33 AF XY: 0.295 AC XY: 21897 AN XY: 74342

African (AFR) AF: 0.275 AC: 11390 AN: 41490

American (AMR) AF: 0.407 AC: 6217 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1082 AN: 3470

East Asian (EAS) AF: 0.313 AC: 1616 AN: 5164

South Asian (SAS) AF: 0.171 AC: 824 AN: 4822

European-Finnish (FIN) AF: 0.300 AC: 3172 AN: 10570

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19339 AN: 67956

Other (OTH) AF: 0.303 AC: 639 AN: 2112

Alfa AF: 0.300 Hom.: 846

Bravo AF: 0.303

Asia WGS AF: 0.297 AC: 1034 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs2289002; hg19: chr1-214177979;