rs200874751

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-74855140-G-T
• chr14-74855140-G-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001243007.2(PROX2):​c.1771C>A​(p.Pro591Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,557,414 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07715577).

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>A	p.Pro591Thr	missense	Exon 6 of 6	NP_001229936.1	G3V3G0
	PROX2	NM_001384314.1		c.1771C>A	p.Pro591Thr	missense	Exon 7 of 7	NP_001371243.1	G3V3G0
	PROX2	NM_001080408.3		c.1090C>A	p.Pro364Thr	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>A	p.Pro591Thr	missense	Exon 6 of 6	ENSP00000451223.2	G3V3G0
	PROX2	ENST00000673765.1		c.1090C>A	p.Pro364Thr	missense	Exon 5 of 5	ENSP00000501015.1	Q3B8N5-2
	YLPM1	ENST00000554107.2	TSL:3	c.205-77G>T		intron	N/A	ENSP00000476212.1	U3KQT9

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.0000890 AC: 21 AN: 236030 AF XY: 0.0000860

Gnomad AFR exome AF: 0.0000683

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 222 AN: 1405288 Hom.: 0 Cov.: 30 AF XY: 0.000133 AC XY: 92 AN XY: 691782

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: 0.000202 AC: 217 AN: 1073624

Other (OTH) AF: 0.0000867 AC: 5 AN: 57702

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74290

African (AFR) AF: 0.0000724 AC: 3 AN: 41426

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68036

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000274 AC: 1

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0094	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.98	T
PhyloP100		2.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.083
Sift	Benign	0.050	D
Sift4G	Uncertain	0.015	D
Polyphen		0.65	P
Vest4		0.14
MVP		0.27
MPC		0.084
ClinPred		0.060	T
GERP RS		2.4
gMVP		0.29
Mutation Taster		=89/11	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;