X-96884903-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.593G>A(p.Arg198His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000794 in 1,208,821 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R198C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., 2 hem., cov: 21)
  • Exomes 𝑓: 0.000078 (0 hom. 29 hem.)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.112

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=0.017601013).
• BS2: High Hemizygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA4	NM_013347.4	c.593G>A	p.Arg198His	missense_variant	1/1	ENST00000373040.4
DIAPH2	NM_006729.5	c.587+3185G>A		intron_variant		ENST00000324765.13
DIAPH2	NM_007309.4	c.587+3185G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA4	ENST00000373040.4	c.593G>A	p.Arg198His	missense_variant	1/1		NM_013347.4	P1
DIAPH2	ENST00000324765.13	c.587+3185G>A		intron_variant		1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.587+3185G>A		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.0000900 AC: 10 AN: 111057 Hom.: 0 Cov.: 21 AF XY: 0.0000602 AC XY: 2 AN XY: 33245

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000192

Gnomad ASJ AF: 0.00303

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: 0.000131 AC: 24 AN: 183060 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00174

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000783 AC: 86 AN: 1097764 Hom.: 0 Cov.: 32 AF XY: 0.0000799 AC XY: 29 AN XY: 363136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00320

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.0000900 AC: 10 AN: 111057 Hom.: 0 Cov.: 21 AF XY: 0.0000602 AC XY: 2 AN XY: 33245

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000192

Gnomad4 ASJ AF: 0.00303

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: 0.000160 Hom.: 5

Bravo AF: 0.000113

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000178

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

Feb 03, 2022

The c.593G>A (p.R198H) 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 593, causing the arginine (R) at amino acid position 198 to be replaced by a histidine (H). 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	0.074
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.35
Dann	Benign	0.56
DEOGEN2	Benign	0.0037	T
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.075
Sift	Benign	0.54	T
Sift4G	Benign	0.23	T
Polyphen		0.96	D
Vest4		0.051
MutPred		0.49		Loss of solvent accessibility (P = 0.0364);
MVP		0.19
MPC		0.30
ClinPred		0.047	T
GERP RS		-2.2
Varity_R		0.025
gMVP		0.19

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: rs199631132; hg19: chrX-96139902; COSMIC: COSV61268886;