X-96884701-C-G

Variant summary

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

The NM_013347.4(RPA4):c.391C>G(p.Leu131Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA4	NM_013347.4	c.391C>G	p.Leu131Val	missense_variant	1/1	ENST00000373040.4
DIAPH2	NM_006729.5	c.587+2983C>G		intron_variant		ENST00000324765.13
DIAPH2	NM_007309.4	c.587+2983C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA4	ENST00000373040.4	c.391C>G	p.Leu131Val	missense_variant	1/1		NM_013347.4	P1
DIAPH2	ENST00000324765.13	c.587+2983C>G		intron_variant		1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.587+2983C>G		intron_variant		1		P3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

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

Jul 12, 2023

The c.391C>G (p.L131V) alteration is located in exon 1 (coding exon 1) of the RPA4 gene. This alteration results from a C to G substitution at nucleotide position 391, causing the leucine (L) at amino acid position 131 to be replaced by a valine (V). 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	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	0.80	D;D;D;D;D;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.085	T
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.63		Gain of sheet (P = 0.0827);
MVP		0.41
MPC		0.57
ClinPred		0.57	D
GERP RS		3.7
Varity_R		0.15
gMVP		0.032

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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-96139700;