1-213997542-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_001270616.2(PROX1):c.1007A>C(p.His336Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,614,082 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: PROX1 NM_001270616.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PROX1
• BP4: Computational evidence support a benign effect (MetaRNN=0.007835031).
• BP6: Variant 1-213997542-A-C is Benign according to our data. Variant chr1-213997542-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3041802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 82 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROX1	NM_001270616.2	c.1007A>C	p.His336Pro	missense_variant	2/5	ENST00000366958.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROX1	ENST00000366958.9	c.1007A>C	p.His336Pro	missense_variant	2/5	1	NM_001270616.2	P1
PROX1	ENST00000435016.2	c.1007A>C	p.His336Pro	missense_variant	2/5	1		P1

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000716 AC: 180 AN: 251270 Hom.: 0 AF XY: 0.000655 AC XY: 89 AN XY: 135824

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.000482 AC: 704 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.000501 AC XY: 364 AN XY: 727192

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000432

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74470

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000449 Hom.: 0

Bravo AF: 0.000903

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PROX1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 11, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	16
Dann	Benign	0.70
DEOGEN2	Benign	0.12	T;T;T;T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N;N
MutationTaster	Benign	0.91	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.31	N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.25
MVP		0.26
MPC		1.0
ClinPred		0.0095	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.47

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: rs144228107; hg19: chr1-214170885;