chr14-74862615-T-C

Variant names:

• chr14-74862615-T-C
• rs78451431
• NM_001243007.2:c.1220A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001243007.2(PROX2):​c.1220A>G​(p.Glu407Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,613,986 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (23 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.66
• 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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044588447).
• BP6: Variant 14-74862615-T-C is Benign according to our data. Variant chr14-74862615-T-C is described in ClinVar as Benign. ClinVar VariationId is 774334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1220A>G	p.Glu407Gly	missense	Exon 3 of 6	NP_001229936.1	G3V3G0
	PROX2	NM_001384314.1		c.1220A>G	p.Glu407Gly	missense	Exon 4 of 7	NP_001371243.1	G3V3G0
	PROX2	NM_001080408.3		c.732+488A>G		intron	N/A	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.1220A>G	p.Glu407Gly	missense	Exon 3 of 6	ENSP00000451223.2	G3V3G0
	PROX2	ENST00000673765.1		c.732+488A>G		intron	N/A	ENSP00000501015.1	Q3B8N5-2

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 526 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00513

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00369 AC: 920 AN: 249278 AF XY: 0.00365

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.00479

GnomAD4 exome AF: 0.00408 AC: 5967 AN: 1461696 Hom.: 23 Cov.: 32 AF XY: 0.00404 AC XY: 2940 AN XY: 727132

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0142 AC: 756 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00445 AC: 4944 AN: 1111862

Other (OTH) AF: 0.00306 AC: 185 AN: 60374

GnomAD4 genome AF: 0.00345 AC: 526 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00349 AC XY: 260 AN XY: 74470

African (AFR) AF: 0.000481 AC: 20 AN: 41566

American (AMR) AF: 0.000457 AC: 7 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00513 AC: 349 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00438 Hom.: 1

Bravo AF: 0.00223

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.00311 AC: 26

ExAC AF: 0.00395 AC: 478

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.033
Sift	Benign	0.27	T
Sift4G	Benign	0.28	T
Polyphen		0.099	B
Vest4		0.19
MVP		0.27
ClinPred		0.024	T
GERP RS		1.7
gMVP		0.30
Mutation Taster		=96/4	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: rs78451431; hg19: chr14-75329318;