Genetic Variant NM_006729.5:c.247G>A (chrX-96738667-G-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006729.5(DIAPH2):c.247G>A(p.Ala83Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,205,238 control chromosomes in the GnomAD database, including 45 homozygotes. There are 3,158 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. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A83A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0063 ( 4 hom., 171 hem., cov: 22)

Exomes 𝑓: 0.0086 ( 41 hom. 2987 hem. )

Consequence

DIAPH2
NM_006729.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.148

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

premature ovarian failure 2A
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

DIAPH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035434961).

BP6

Variant X-96738667-G-A is Benign according to our data. Variant chrX-96738667-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 790385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 Unknown gene

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.247G>A	p.Ala83Thr	missense	Exon 3 of 27	NP_006720.1	O60879-1
	DIAPH2	NM_007309.4		c.247G>A	p.Ala83Thr	missense	Exon 3 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.247G>A	p.Ala83Thr	missense	Exon 3 of 27	ENSP00000321348.8	O60879-1
	DIAPH2	ENST00000373049.8	TSL:1	c.247G>A	p.Ala83Thr	missense	Exon 3 of 27	ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes

AF:

0.00634

AC:

705

AN:

111135

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00144

Gnomad AMI

AF:

0.00146

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.000755

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00114

Gnomad FIN

AF:

0.00946

Gnomad MID

AF:

0.00847

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00672

GnomAD2 exomes

AF:

0.00623

AC:

1125

AN:

180556

AF XY:

0.00577

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00358

Gnomad ASJ exome

AF:

0.000673

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00732

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.00519

GnomAD4 exome

AF:

0.00862

AC:

9435

AN:

1094054

Hom.:

Cov.:

AF XY:

0.00830

AC XY:

2987

AN XY:

359730

show subpopulations

African (AFR)

AF:

0.000685

AC:

AN:

26296

American (AMR)

AF:

0.00373

AC:

131

AN:

35075

Ashkenazi Jewish (ASJ)

AF:

0.000674

AC:

AN:

19295

East Asian (EAS)

AF:

0.00

AC:

AN:

30120

South Asian (SAS)

AF:

0.00200

AC:

107

AN:

53593

European-Finnish (FIN)

AF:

0.00702

AC:

284

AN:

40484

Middle Eastern (MID)

AF:

0.00509

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.0102

AC:

8539

AN:

839166

Other (OTH)

AF:

0.00701

AC:

322

AN:

45903

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

302

604

905

1207

1509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

308

616

924

1232

1540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00634

AC:

705

AN:

111184

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

171

AN XY:

33454

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

30632

American (AMR)

AF:

0.00268

AC:

AN:

10445

Ashkenazi Jewish (ASJ)

AF:

0.000755

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3536

South Asian (SAS)

AF:

0.00115

AC:

AN:

2617

European-Finnish (FIN)

AF:

0.00946

AC:

AN:

5922

Middle Eastern (MID)

AF:

0.00930

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0106

AC:

559

AN:

52976

Other (OTH)

AF:

0.00663

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00821

Hom.:

383

Bravo

AF:

0.00533

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00104

AC:

ESP6500EA

AF:

0.0107

AC:

ExAC

AF:

0.00680

AC:

826

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Premature ovarian failure 2A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0035

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.49

PhyloP100

0.15

PrimateAI

Benign

0.30

PROVEAN

Benign

0.33

REVEL

Benign

0.14

Sift

Benign

0.33

Sift4G

Benign

0.37

Polyphen

0.0030

Vest4

0.036

MVP

0.57

MPC

0.32

ClinPred

0.012

GERP RS

4.8

Varity_R

0.087

gMVP

0.26

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over