Genetic Variant RPA4:p.Pro32Ala (chrX-96884404-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_013347.4(RPA4):c.94C>G(p.Pro32Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)

Consequence

RPA4
NM_013347.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.333

Publications

0 publications found

Variant links:

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]

RPA4 links:

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]

DIAPH2 Gene-Disease associations (from GenCC):

premature ovarian failure 2A
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

DIAPH2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.112578034).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013347.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPA4	NM_013347.4	MANE Select	c.94C>G	p.Pro32Ala	missense	Exon 1 of 1	NP_037479.1	Q13156
DIAPH2	NM_006729.5	MANE Select	c.587+2686C>G		intron	N/A	NP_006720.1	O60879-1
DIAPH2	NM_007309.4		c.587+2686C>G		intron	N/A	NP_009293.1	O60879-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPA4	ENST00000373040.4	TSL:6 MANE Select	c.94C>G	p.Pro32Ala	missense	Exon 1 of 1	ENSP00000362131.3	Q13156
DIAPH2	ENST00000324765.13	TSL:1 MANE Select	c.587+2686C>G		intron	N/A	ENSP00000321348.8	O60879-1
DIAPH2	ENST00000373049.8	TSL:1	c.587+2686C>G		intron	N/A	ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.92

CADD

Benign

9.3

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.012

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.29

M_CAP

Benign

0.035

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.33

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

REVEL

Benign

0.010

Sift

Benign

0.14

Sift4G

Benign

0.12

Polyphen

0.46

Vest4

0.13

MutPred

0.30

Gain of sheet (P = 0.0477)

MVP

0.23

MPC

0.39

ClinPred

0.069

GERP RS

0.28

PromoterAI

0.019

Neutral

(source)

Varity_R

0.034

gMVP

0.025

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over