chrX-96884614-A-G

Variant names:

• chrX-96884614-A-G
• rs762302359
• NM_013347.4:c.304A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_013347.4(RPA4):​c.304A>G​(p.Ile102Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,207,514 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000091 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.000021 (0 hom. 7 hem.)
• Consequence: RPA4 NM_013347.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.517
• Publications: 0 publications found

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]

DIAPH2 Gene-Disease associations (from GenCC):

• premature ovarian failure 2A

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.101694465).
• BS2: High Hemizygotes in GnomAdExome4 at 7 gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA4	NM_013347.4	MANE Select	c.304A>G	p.Ile102Val	missense	Exon 1 of 1	NP_037479.1	Q13156
	DIAPH2	NM_006729.5	MANE Select	c.587+2896A>G		intron	N/A	NP_006720.1	O60879-1
	DIAPH2	NM_007309.4		c.587+2896A>G		intron	N/A	NP_009293.1	O60879-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA4	ENST00000373040.4	TSL:6 MANE Select	c.304A>G	p.Ile102Val	missense	Exon 1 of 1	ENSP00000362131.3	Q13156
	DIAPH2	ENST00000324765.13	TSL:1 MANE Select	c.587+2896A>G		intron	N/A	ENSP00000321348.8	O60879-1
	DIAPH2	ENST00000373049.8	TSL:1	c.587+2896A>G		intron	N/A	ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes AF: 0.00000911 AC: 1 AN: 109719 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000984

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000602 AC: 11 AN: 182714 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.000362

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 23 AN: 1097795 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 7 AN XY: 363155

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.0000568 AC: 2 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.000206 AC: 4 AN: 19382

East Asian (EAS) AF: 0.000199 AC: 6 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40487

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841770

Other (OTH) AF: 0.0000651 AC: 3 AN: 46083

GnomAD4 genome AF: 0.00000911 AC: 1 AN: 109719 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 31959

African (AFR) AF: 0.00 AC: 0 AN: 30096

American (AMR) AF: 0.0000984 AC: 1 AN: 10164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3466

South Asian (SAS) AF: 0.00 AC: 0 AN: 2472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52802

Other (OTH) AF: 0.00 AC: 0 AN: 1475

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.96
DANN	Benign	0.94
DEOGEN2	Benign	0.0056	T
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.52
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.061
Sift	Uncertain	0.013	D
Sift4G	Benign	0.18	T
Polyphen		0.25	B
Vest4		0.20
MutPred		0.67		Gain of MoRF binding (P = 0.1195)
MVP		0.11
MPC		0.29
ClinPred		0.045	T
GERP RS		1.3
Varity_R		0.070
gMVP		0.023
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs762302359; hg19: chrX-96139613;