rs12748973

Positions:

• chr1-214008891-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001270616.2(PROX1):​c.1834-2630C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 152,218 control chromosomes in the GnomAD database, including 86 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 0.027 (86 hom., cov: 32)
• Consequence: PROX1 NM_001270616.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.113

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0273 (4148/152218) while in subpopulation NFE AF= 0.0435 (2960/68014). AF 95% confidence interval is 0.0422. There are 86 homozygotes in gnomad4. There are 1956 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROX1	NM_001270616.2	c.1834-2630C>T		intron_variant		ENST00000366958.9	NP_001257545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROX1	ENST00000366958.9	c.1834-2630C>T		intron_variant		1	NM_001270616.2	ENSP00000355925.4
PROX1	ENST00000435016.2	c.1834-2630C>T		intron_variant		1		ENSP00000400694.1

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4147 AN: 152102 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.00867

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.0258

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0229

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

GnomAD4 genome AF: 0.0273 AC: 4148 AN: 152218 Hom.: 86 Cov.: 32 AF XY: 0.0263 AC XY: 1956 AN XY: 74424

Gnomad4 AFR AF: 0.00864

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0334

Gnomad4 FIN AF: 0.0258

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0283 Hom.: 9

Bravo AF: 0.0251

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.80

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

LitVar

Other links and lift over

dbSNP: rs12748973; hg19: chr1-214182234;