X-96884323-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_013347.4(RPA4):c.13G>A(p.Gly5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,206,838 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.000057 ( 0 hom. 22 hem. )

Consequence

RPA4
NM_013347.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.23

Variant links:

Genes affected

RPA4 (HGNC:30305): (replication protein A4) This gene encodes a single-stranded DNA-binding protein that is the 30-kDa subunit of the replication protein A complex. Replication protein A is an essential factor for DNA double-strand break repair and cell cycle checkpoint activation. The encoded protein localizes to DNA repair foci and may be involved in the cellular DNA damage response. This protein may also play a role in inhibiting viral replication.[provided by RefSeq, Apr 2010]

RPA4 links:

DIAPH2 (HGNC:2877): (diaphanous related formin 2) The product of this gene belongs to the diaphanous subfamily of the formin homology family of proteins. This gene may play a role in the development and normal function of the ovaries. Defects in this gene have been linked to premature ovarian failure 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

DIAPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.084296525).

BP6

Variant X-96884323-G-A is Benign according to our data. Variant chrX-96884323-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2661022.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA4	NM_013347.4 link	c.13G>A	p.Gly5Arg	missense_variant	Exon 1 of 1	ENST00000373040.4	NP_037479.1	Q13156
DIAPH2	NM_006729.5 link	c.587+2605G>A		intron_variant	Intron 5 of 26	ENST00000324765.13	NP_006720.1	O60879-1
DIAPH2	NM_007309.4 link	c.587+2605G>A		intron_variant	Intron 5 of 26		NP_009293.1	O60879-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPA4	ENST00000373040.4 link	c.13G>A	p.Gly5Arg	missense_variant	Exon 1 of 1	6	NM_013347.4	ENSP00000362131.3	Q13156
DIAPH2	ENST00000324765.13 link	c.587+2605G>A		intron_variant	Intron 5 of 26	1	NM_006729.5	ENSP00000321348.8	O60879-1
DIAPH2	ENST00000373049.8 link	c.587+2605G>A		intron_variant	Intron 5 of 26	1		ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111345

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33503

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000333

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.000672

GnomAD3 exomes

AF:

0.0000449

AC:

AN:

178073

Hom.:

AF XY:

0.0000317

AC XY:

AN XY:

62997

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000566

AC:

AN:

1095493

Hom.:

Cov.:

AF XY:

0.0000609

AC XY:

AN XY:

361223

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000173

Gnomad4 NFE exome

AF:

0.0000642

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000117

AC:

AN:

111345

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

33503

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000333

Gnomad4 NFE

AF:

0.000188

Gnomad4 OTH

AF:

0.000672

Alfa

AF:

0.000540

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPA4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.50

M_CAP

Benign

0.060

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.014

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

0.82

Vest4

0.13

MutPred

0.37

Gain of MoRF binding (P = 7e-04);

MVP

0.22

MPC

0.61

ClinPred

0.19

GERP RS

1.8

Varity_R

0.11

gMVP

0.086

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over