X-96884410-A-C

Variant names:

• chrX-96884410-A-C
• rs749838488
• NM_013347.4:c.100A>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 15/21 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
• 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: 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=0.0706875).

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.100A>C	p.Ile34Leu	missense	Exon 1 of 1	NP_037479.1	Q13156
	DIAPH2	NM_006729.5	MANE Select	c.587+2692A>C		intron	N/A	NP_006720.1	O60879-1
	DIAPH2	NM_007309.4		c.587+2692A>C		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.100A>C	p.Ile34Leu	missense	Exon 1 of 1	ENSP00000362131.3	Q13156
	DIAPH2	ENST00000324765.13	TSL:1 MANE Select	c.587+2692A>C		intron	N/A	ENSP00000321348.8	O60879-1
	DIAPH2	ENST00000373049.8	TSL:1	c.587+2692A>C		intron	N/A	ENSP00000362140.4	O60879-2

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

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841592

Other (OTH) AF: 0.00 AC: 0 AN: 46075

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-4.1
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
Mutation Taster		=100/0	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: rs749838488; hg19: chrX-96139409;