Genetic Variant DIAPH2:p.Asp57Glu (chrX-96738591-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_006729.5(DIAPH2):c.171C>A(p.Asp57Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000505 in 1,188,771 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

DIAPH2
NM_006729.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.58

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3263213).

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH2	NM_006729.5 link	c.171C>A	p.Asp57Glu	missense_variant	Exon 3 of 27	ENST00000324765.13	NP_006720.1	O60879-1
DIAPH2	NM_007309.4 link	c.171C>A	p.Asp57Glu	missense_variant	Exon 3 of 27		NP_009293.1	O60879-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH2	ENST00000324765.13 link	c.171C>A	p.Asp57Glu	missense_variant	Exon 3 of 27	1	NM_006729.5	ENSP00000321348.8		O60879-1
DIAPH2	ENST00000373049.8 link	c.171C>A	p.Asp57Glu	missense_variant	Exon 3 of 27	1		ENSP00000362140.4		O60879-2

Frequencies

GnomAD3 genomes

AF:

0.0000361

AC:

AN:

110873

Hom.:

Cov.:

AF XY:

0.0000301

AC XY:

AN XY:

33195

show subpopulations

Gnomad AFR

AF:

0.000131

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000611

AC:

AN:

163695

Hom.:

AF XY:

0.00

AC XY:

AN XY:

54381

show subpopulations

Gnomad AFR exome

AF:

0.0000805

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.28e-7

AC:

AN:

1077845

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

350009

show subpopulations

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:

0.00000120

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000451

AC:

AN:

110926

Hom.:

Cov.:

AF XY:

0.0000601

AC XY:

AN XY:

33258

show subpopulations

Gnomad4 AFR

AF:

0.000164

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.171C>A (p.D57E) alteration is located in exon 3 (coding exon 3) of the DIAPH2 gene. This alteration results from a C to A substitution at nucleotide position 171, causing the aspartic acid (D) at amino acid position 57 to be replaced by a glutamic acid (E). 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

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.022

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.20

.;.;.;T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.75

T;T;T;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.33

T;T;T;T;T

MetaSVM

Uncertain

0.053

MutationAssessor

Benign

1.3

.;.;L;L;.

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.6

N;N;N;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.58

T;T;T;T;.

Sift4G

Benign

0.65

T;T;T;T;T

Polyphen

1.0, 1.0

.;.;D;D;.

Vest4

0.35

MutPred

0.28

Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MVP

0.91

MPC

0.31

ClinPred

0.17

GERP RS

5.6

Varity_R

0.35

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over