X-96758196-A-G

Variant names:

• chrX-96758196-A-G
• rs201217520
• NM_006729.5:c.385A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006729.5(DIAPH2):​c.385A>G​(p.Asn129Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,093,733 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: DIAPH2 NM_006729.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• Publications: 1 publications found

Genes affected

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=0.1899398).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006729.5. 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
	DIAPH2	NM_006729.5	MANE Select	c.385A>G	p.Asn129Asp	missense	Exon 4 of 27	NP_006720.1	O60879-1
	DIAPH2	NM_007309.4		c.385A>G	p.Asn129Asp	missense	Exon 4 of 27	NP_009293.1	O60879-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH2	ENST00000324765.13	TSL:1 MANE Select	c.385A>G	p.Asn129Asp	missense	Exon 4 of 27	ENSP00000321348.8	O60879-1
	DIAPH2	ENST00000373049.8	TSL:1	c.385A>G	p.Asn129Asp	missense	Exon 4 of 27	ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000566 AC: 1 AN: 176670 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000457 AC: 5 AN: 1093733 Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1 AN XY: 359847

African (AFR) AF: 0.00 AC: 0 AN: 26267

American (AMR) AF: 0.00 AC: 0 AN: 34428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19259

East Asian (EAS) AF: 0.00 AC: 0 AN: 30041

South Asian (SAS) AF: 0.00 AC: 0 AN: 52995

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840361

Other (OTH) AF: 0.0000436 AC: 2 AN: 45846

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Premature ovarian failure 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.69	N
PhyloP100		2.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.90	N
REVEL	Benign	0.12
Sift	Benign	0.035	D
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.46		Loss of MoRF binding (P = 0.0394)
MVP		0.83
MPC		0.37
ClinPred		0.41	T
GERP RS		0.28
Varity_R		0.13
gMVP		0.30
Mutation Taster		=95/5	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: rs201217520; hg19: chrX-96013195;