X-96884336-A-G

Variant summary

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

The NM_013347.4(RPA4):c.26A>G(p.Tyr9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,208,082 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00012 (0 hom. 43 hem.)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.612

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=0.013720214).
• BS2: High Hemizygotes in GnomAd at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA4	NM_013347.4	c.26A>G	p.Tyr9Cys	missense_variant	1/1	ENST00000373040.4
DIAPH2	NM_006729.5	c.587+2618A>G		intron_variant		ENST00000324765.13
DIAPH2	NM_007309.4	c.587+2618A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA4	ENST00000373040.4	c.26A>G	p.Tyr9Cys	missense_variant	1/1		NM_013347.4	P1
DIAPH2	ENST00000324765.13	c.587+2618A>G		intron_variant		1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.587+2618A>G		intron_variant		1		P3

Frequencies

GnomAD3 genomes AF: 0.000360 AC: 40 AN: 111178 Hom.: 0 Cov.: 22 AF XY: 0.000270 AC XY: 9 AN XY: 33384

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000288

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: 0.000170

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000172 AC: 31 AN: 180337 Hom.: 0 AF XY: 0.000108 AC XY: 7 AN XY: 65039

Gnomad AFR exome AF: 0.000838

Gnomad AMR exome AF: 0.000294

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: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 135 AN: 1096849 Hom.: 0 Cov.: 29 AF XY: 0.000119 AC XY: 43 AN XY: 362315

Gnomad4 AFR exome AF: 0.000948

Gnomad4 AMR exome AF: 0.000313

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: 0.000102

Gnomad4 OTH exome AF: 0.000174

GnomAD4 genome AF: 0.000351 AC: 39 AN: 111233 Hom.: 0 Cov.: 22 AF XY: 0.000239 AC XY: 8 AN XY: 33449

Gnomad4 AFR AF: 0.000882

Gnomad4 AMR AF: 0.000288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000170

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000187 Hom.: 10

Bravo AF: 0.000336

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000173 AC: 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

Dec 27, 2022

The c.26A>G (p.Y9C) alteration is located in exon 1 (coding exon 1) of the RPA4 gene. This alteration results from a A to G substitution at nucleotide position 26, causing the tyrosine (Y) at amino acid position 9 to be replaced by a cysteine (C). 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	0.066
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.6
Dann	Benign	0.96
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.027
Sift	Benign	0.051	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0050	B
Vest4		0.13
MVP		0.19
MPC		0.15
ClinPred		0.0050	T
GERP RS		-2.2
Varity_R		0.10
gMVP		0.12

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: rs142187288; hg19: chrX-96139335;