X-96885091-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_013347.4(RPA4):c.781G>A(p.Asp261Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 1,198,917 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 76 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000091 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.00022 (0 hom. 73 hem.)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.501

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=0.039249986).
• BS2: High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA4	NM_013347.4	c.781G>A	p.Asp261Asn	missense_variant	1/1	ENST00000373040.4
DIAPH2	NM_006729.5	c.587+3373G>A		intron_variant		ENST00000324765.13
DIAPH2	NM_007309.4	c.587+3373G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA4	ENST00000373040.4	c.781G>A	p.Asp261Asn	missense_variant	1/1		NM_013347.4	P1
DIAPH2	ENST00000324765.13	c.587+3373G>A		intron_variant		1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.587+3373G>A		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.0000906 AC: 10 AN: 110430 Hom.: 0 Cov.: 21 AF XY: 0.0000919 AC XY: 3 AN XY: 32632

Gnomad AFR AF: 0.0000990

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: 0.000516

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000756

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 23 AN: 178639 Hom.: 0 AF XY: 0.000142 AC XY: 9 AN XY: 63569

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: 0.000507

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000222 AC: 242 AN: 1088487 Hom.: 0 Cov.: 30 AF XY: 0.000206 AC XY: 73 AN XY: 354941

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: 0.0000563

Gnomad4 FIN exome AF: 0.000668

Gnomad4 NFE exome AF: 0.000247

Gnomad4 OTH exome AF: 0.000131

GnomAD4 genome AF: 0.0000906 AC: 10 AN: 110430 Hom.: 0 Cov.: 21 AF XY: 0.0000919 AC XY: 3 AN XY: 32632

Gnomad4 AFR AF: 0.0000990

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000516

Gnomad4 NFE AF: 0.0000756

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.781G>A (p.D261N) 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 781, causing the aspartic acid (D) at amino acid position 261 to be replaced by an asparagine (N). 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	Benign	0.13
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.082	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.074
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.054	B
Vest4		0.069
MVP		0.50
MPC		0.12
ClinPred		0.065	T
GERP RS		0.57
Varity_R		0.11
gMVP		0.068

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: rs200339720; hg19: chrX-96140090; COSMIC: COSV61274879;