14-74855140-G-A

Variant names:

• chr14-74855140-G-A
• rs200874751
• NM_001243007.2:c.1771C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001243007.2(PROX2):​c.1771C>T​(p.Pro591Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,405,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P591T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• Publications: 0 publications found

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]

YLPM1 (HGNC:17798): (YLP motif containing 1) Enables RNA binding activity. Predicted to be involved in regulation of telomere maintenance. Predicted to act upstream of or within negative regulation of transcription by RNA polymerase II. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040171504).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001243007.2. 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
	PROX2	NM_001243007.2	MANE Select	c.1771C>T	p.Pro591Ser	missense	Exon 6 of 6	NP_001229936.1	G3V3G0
	PROX2	NM_001384314.1		c.1771C>T	p.Pro591Ser	missense	Exon 7 of 7	NP_001371243.1	G3V3G0
	PROX2	NM_001080408.3		c.1090C>T	p.Pro364Ser	missense	Exon 5 of 5	NP_001073877.2	Q3B8N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROX2	ENST00000556489.4	TSL:1 MANE Select	c.1771C>T	p.Pro591Ser	missense	Exon 6 of 6	ENSP00000451223.2	G3V3G0
	PROX2	ENST00000673765.1		c.1090C>T	p.Pro364Ser	missense	Exon 5 of 5	ENSP00000501015.1	Q3B8N5-2
	YLPM1	ENST00000554107.2	TSL:3	c.205-77G>A		intron	N/A	ENSP00000476212.1	U3KQT9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405292 Hom.: 0 Cov.: 30 AF XY: 0.00000289 AC XY: 2 AN XY: 691784

African (AFR) AF: 0.00 AC: 0 AN: 32652

American (AMR) AF: 0.00 AC: 0 AN: 42824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24832

East Asian (EAS) AF: 0.00 AC: 0 AN: 38558

South Asian (SAS) AF: 0.00 AC: 0 AN: 77542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51980

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1073628

Other (OTH) AF: 0.00 AC: 0 AN: 57702

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.076
Sift	Benign	0.59	T
Sift4G	Benign	0.43	T
Polyphen		0.047	B
Vest4		0.043
MutPred		0.12		Gain of phosphorylation at P591 (P = 0.0069)
MVP		0.18
MPC		0.052
ClinPred		0.089	T
GERP RS		2.4
gMVP		0.31
Mutation Taster		=88/12	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: rs200874751; hg19: chr14-75321843;