Variant chrX-96738667-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 790385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-96738667-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH2	NM_006729.5 linkuse as main transcript	c.247G>A	p.Ala83Thr	missense_variant	3/27	ENST00000324765.13	NP_006720.1	O60879-1
DIAPH2	NM_007309.4 linkuse as main transcript	c.247G>A	p.Ala83Thr	missense_variant	3/27		NP_009293.1	O60879-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH2	ENST00000324765.13 linkuse as main transcript	c.247G>A	p.Ala83Thr	missense_variant	3/27	1	NM_006729.5	ENSP00000321348.8		O60879-1
DIAPH2	ENST00000373049.8 linkuse as main transcript	c.247G>A	p.Ala83Thr	missense_variant	3/27	1		ENSP00000362140.4		O60879-2

Frequencies

GnomAD3 genomes

AF:

0.00634

AC:

705

AN:

111135

Hom.:

Cov.:

AF XY:

0.00512

AC XY:

171

AN XY:

33395

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

GnomAD3 exomes

AF:

0.00623

AC:

1125

AN:

180556

Hom.:

AF XY:

0.00577

AC XY:

376

AN XY:

65186

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 SAS exome

AF:

0.00157

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

Gnomad4 AFR exome

AF:

0.000685

Gnomad4 AMR exome

AF:

0.00373

Gnomad4 ASJ exome

AF:

0.000674

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00200

Gnomad4 FIN exome

AF:

0.00702

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00701

GnomAD4 genome

AF:

0.00634

AC:

705

AN:

111184

Hom.:

Cov.:

AF XY:

0.00511

AC XY:

171

AN XY:

33454

show subpopulations

Gnomad4 AFR

AF:

0.00144

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.000755

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00115

Gnomad4 FIN

AF:

0.00946

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.00663

Alfa

AF:

0.00873

Hom.:

378

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Premature ovarian failure 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

5.0

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;.;.;T;T

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.66

T;T;T;T;T

MetaRNN

Benign

0.0035

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.49

.;.;N;N;.

PrimateAI

Benign

0.30

PROVEAN

Benign

0.33

N;N;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.33

T;T;T;T;.

Sift4G

Benign

0.37

T;T;T;T;T

Polyphen

0.0030, 0.41

.;.;B;B;.

Vest4

0.036

MVP

0.57

MPC

0.32

ClinPred

0.012

GERP RS

4.8

Varity_R

0.087

gMVP

0.26

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