14-74863455-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001243007.2(PROX2):c.380A>G(p.Lys127Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,613,578 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: PROX2 NM_001243007.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.15

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028780103).
• BP6: Variant 14-74863455-T-C is Benign according to our data. Variant chr14-74863455-T-C is described in ClinVar as [Benign]. Clinvar id is 786621.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1689/152368) while in subpopulation AFR AF= 0.0379 (1576/41590). AF 95% confidence interval is 0.0363. There are 31 homozygotes in gnomad4. There are 793 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROX2	NM_001243007.2	c.380A>G	p.Lys127Arg	missense_variant	3/6	ENST00000556489.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROX2	ENST00000556489.4	c.380A>G	p.Lys127Arg	missense_variant	3/6	1	NM_001243007.2	P1
PROX2	ENST00000673765.1	c.380A>G	p.Lys127Arg	missense_variant	3/5

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1685 AN: 152250 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00286 AC: 710 AN: 248026 Hom.: 11 AF XY: 0.00226 AC XY: 304 AN XY: 134534

Gnomad AFR exome AF: 0.0386

Gnomad AMR exome AF: 0.00282

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00108 AC: 1584 AN: 1461210 Hom.: 26 Cov.: 32 AF XY: 0.000975 AC XY: 709 AN XY: 726860

Gnomad4 AFR exome AF: 0.0374

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00259

GnomAD4 genome AF: 0.0111 AC: 1689 AN: 152368 Hom.: 31 Cov.: 32 AF XY: 0.0106 AC XY: 793 AN XY: 74512

Gnomad4 AFR AF: 0.0379

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00180 Hom.: 8

Bravo AF: 0.0123

ESP6500AA AF: 0.0106 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00356 AC: 430

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 18, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.92	N;N
Sift	Uncertain	0.0060	D;T
Sift4G	Benign	0.22	T;T
Polyphen		0.047	B;B
Vest4		0.29
MVP		0.10
MPC		0.27
ClinPred		0.045	T
GERP RS		4.4
gMVP		0.18

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: rs115990005; hg19: chr14-75330158;