X-96884828-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013347.4(RPA4):c.518G>A(p.Arg173His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,098,113 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.129

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0827764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA4	NM_013347.4	c.518G>A	p.Arg173His	missense_variant	1/1	ENST00000373040.4
DIAPH2	NM_006729.5	c.587+3110G>A		intron_variant		ENST00000324765.13
DIAPH2	NM_007309.4	c.587+3110G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA4	ENST00000373040.4	c.518G>A	p.Arg173His	missense_variant	1/1		NM_013347.4	P1
DIAPH2	ENST00000324765.13	c.587+3110G>A		intron_variant		1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.587+3110G>A		intron_variant		1		P3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098113 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363469

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: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

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

Mar 29, 2022

The c.518G>A (p.R173H) 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 518, causing the arginine (R) at amino acid position 173 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	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.42
Dann	Benign	0.96
DEOGEN2	Benign	0.00047	T
FATHMM_MKL	Benign	0.00055	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.0070
Sift	Benign	0.23	T
Sift4G	Benign	0.12	T
Polyphen		0.40	B
Vest4		0.073
MutPred		0.43		Gain of glycosylation at T176 (P = 0.0593);
MVP		0.23
MPC		0.23
ClinPred		0.12	T
GERP RS		-1.4
Varity_R		0.029
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-96139827; COSMIC: COSV61266302;