chrX-96884512-G-A

Position:

chrX-96884512-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000324765.13(DIAPH2):c.587+2794G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,208,383 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.000031 ( 0 hom. 14 hem. )

Consequence

DIAPH2
ENST00000324765.13 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.892

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12945956).

BS2

High Hemizygotes in GnomAdExome4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RPA4	NM_013347.4 linkuse as main transcript	c.202G>A	p.Gly68Arg	missense_variant	1/1	ENST00000373040.4	NP_037479.1
DIAPH2	NM_006729.5 linkuse as main transcript	c.587+2794G>A		intron_variant		ENST00000324765.13	NP_006720.1
DIAPH2	NM_007309.4 linkuse as main transcript	c.587+2794G>A		intron_variant			NP_009293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA4	ENST00000373040.4 linkuse as main transcript	c.202G>A	p.Gly68Arg	missense_variant	1/1		NM_013347.4	ENSP00000362131	P1
DIAPH2	ENST00000324765.13 linkuse as main transcript	c.587+2794G>A		intron_variant		1	NM_006729.5	ENSP00000321348	A2	O60879-1
DIAPH2	ENST00000373049.8 linkuse as main transcript	c.587+2794G>A		intron_variant		1		ENSP00000362140	P3	O60879-2

Frequencies

GnomAD3 genomes

AF:

0.00000903

AC:

AN:

110758

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

32960

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000970

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183194

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1097625

Hom.:

Cov.:

AF XY:

0.0000386

AC XY:

AN XY:

362981

show subpopulations

Gnomad4 AFR exome

AF:

0.000152

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.0000739

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000202

Gnomad4 OTH exome

AF:

0.000152

GnomAD4 genome

AF:

0.00000903

AC:

AN:

110758

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

32960

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000970

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2022

The c.202G>A (p.G68R) alteration is located in exon 1 (coding exon 1) of the RPA4 gene. This alteration results from a G to A substitution at nucleotide position 202, causing the glycine (G) at amino acid position 68 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.48

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

MutationTaster

Benign

1.0

N;N;N;N;N;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.3

REVEL

Benign

0.10

Sift

Benign

0.20

Sift4G

Benign

0.080

Polyphen

0.79

Vest4

0.087

MutPred

0.56

Gain of MoRF binding (P = 0.0082);

MVP

0.67

MPC

0.50

ClinPred

0.11

GERP RS

0.57

Varity_R

0.078

gMVP

0.085

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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