rs12748973

Variant names:

• chr1-214008891-C-T
• rs12748973
• NM_001270616.2:c.1834-2630C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4148 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX1	NM_001270616.2	MANE Select	c.1834-2630C>T		intron	N/A	NP_001257545.1
	PROX1	NM_002763.5		c.1834-2630C>T		intron	N/A	NP_002754.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX1	ENST00000366958.9	TSL:1 MANE Select	c.1834-2630C>T		intron	N/A	ENSP00000355925.4
	PROX1	ENST00000435016.2	TSL:1	c.1834-2630C>T		intron	N/A	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

African (AFR) AF: 0.00864 AC: 359 AN: 41530

American (AMR) AF: 0.0203 AC: 310 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.0334 AC: 161 AN: 4820

European-Finnish (FIN) AF: 0.0258 AC: 274 AN: 10600

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0435 AC: 2960 AN: 68014

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0231 Hom.: 18

Bravo AF: 0.0251

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.80
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism

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: rs12748973; hg19: chr1-214182234;