14-74863240-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001243007.2(PROX2):c.595G>A(p.Asp199Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,461,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.292

Genes affected

PROX2 (HGNC:26715): (prospero homeobox 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0376305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROX2	NM_001243007.2	c.595G>A	p.Asp199Asn	missense_variant	3/6	ENST00000556489.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROX2	ENST00000556489.4	c.595G>A	p.Asp199Asn	missense_variant	3/6	1	NM_001243007.2	P1
PROX2	ENST00000673765.1	c.595G>A	p.Asp199Asn	missense_variant	3/5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461504 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727038

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.595G>A (p.D199N) alteration is located in exon 1 (coding exon 1) of the PROX2 gene. This alteration results from a G to A substitution at nucleotide position 595, causing the aspartic acid (D) at amino acid position 199 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.22	N;N
Sift	Benign	0.27	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.0020	B;B
Vest4		0.071
MutPred		0.14		Loss of phosphorylation at S201 (P = 0.0956);Loss of phosphorylation at S201 (P = 0.0956);
MVP		0.048
MPC		0.058
ClinPred		0.096	T
GERP RS		-4.7
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2091812898; hg19: chr14-75329943;