X-96884323-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23

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]

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]

ACMG classification

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 GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA4	NM_013347.4	c.13G>A	p.Gly5Arg	missense_variant	1/1	ENST00000373040.4
DIAPH2	NM_006729.5	c.587+2605G>A		intron_variant		ENST00000324765.13
DIAPH2	NM_007309.4	c.587+2605G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA4	ENST00000373040.4	c.13G>A	p.Gly5Arg	missense_variant	1/1		NM_013347.4	P1
DIAPH2	ENST00000324765.13	c.587+2605G>A		intron_variant		1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.587+2605G>A		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.000117 AC: 13 AN: 111345 Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4 AN XY: 33503

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: 8 AN: 178073 Hom.: 0 AF XY: 0.0000317 AC XY: 2 AN XY: 62997

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: 62 AN: 1095493 Hom.: 0 Cov.: 29 AF XY: 0.0000609 AC XY: 22 AN XY: 361223

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: 13 AN: 111345 Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4 AN XY: 33503

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.: 2

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

RPA4: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.014
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.82	P
Vest4		0.13
MutPred		0.37		Gain of MoRF binding (P = 7e-04);
MVP		0.22
MPC		0.61
ClinPred		0.19	T
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

Other links and lift over

dbSNP: rs375731658; hg19: chrX-96139322;