chrX-96884410-A-C

Variant names:

• chrX-96884410-A-C
• NM_013347.4:c.100A>C

Variant summary

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

The NM_013347.4(RPA4):​c.100A>C​(p.Ile34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,644 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I34V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.10

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=0.0706875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA4	NM_013347.4	c.100A>C	p.Ile34Leu	missense_variant	Exon 1 of 1	ENST00000373040.4	NP_037479.1
DIAPH2	NM_006729.5	c.587+2692A>C		intron_variant	Intron 5 of 26	ENST00000324765.13	NP_006720.1
DIAPH2	NM_007309.4	c.587+2692A>C		intron_variant	Intron 5 of 26		NP_009293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA4	ENST00000373040.4	c.100A>C	p.Ile34Leu	missense_variant	Exon 1 of 1	6	NM_013347.4	ENSP00000362131.3
DIAPH2	ENST00000324765.13	c.587+2692A>C		intron_variant	Intron 5 of 26	1	NM_006729.5	ENSP00000321348.8
DIAPH2	ENST00000373049.8	c.587+2692A>C		intron_variant	Intron 5 of 26	1		ENSP00000362140.4

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097644 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1 AN XY: 363004

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0020
DANN	Benign	0.61
DEOGEN2	Benign	0.0012	T
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.00096	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.0030
Sift	Benign	0.43	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.26		Gain of phosphorylation at T31 (P = 0.0851);
MVP		0.13
MPC		0.12
ClinPred		0.16	T
GERP RS		-6.8
Varity_R		0.074
gMVP		0.027

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-96139409;