Variant X-96685074-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006729.5(DIAPH2):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DIAPH2
NM_006729.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21834078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH2	NM_006729.5 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/27	ENST00000324765.13	NP_006720.1
DIAPH2	NM_007309.4 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/27		NP_009293.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH2	ENST00000324765.13 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/27	1	NM_006729.5	ENSP00000321348	A2	O60879-1
DIAPH2	ENST00000373049.8 linkuse as main transcript	c.16G>A	p.Ala6Thr	missense_variant	1/27	1		ENSP00000362140	P3	O60879-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

893158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

275320

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2022

The c.16G>A (p.A6T) alteration is located in exon 1 (coding exon 1) of the DIAPH2 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the alanine (A) at amino acid position 6 to be replaced by a threonine (T). 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

Benign

0.098

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;.;.;T;T

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.69

T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.0

.;.;N;N;.

MutationTaster

Benign

0.95

N;N;N;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.84

N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.073

T;T;T;T;T

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

0.0030, 0.0010

.;.;B;B;.

Vest4

0.33

MutPred

0.17

Gain of phosphorylation at A6 (P = 0.0087);Gain of phosphorylation at A6 (P = 0.0087);Gain of phosphorylation at A6 (P = 0.0087);Gain of phosphorylation at A6 (P = 0.0087);Gain of phosphorylation at A6 (P = 0.0087);

MVP

0.55

MPC

0.32

ClinPred

0.36

GERP RS

2.8

Varity_R

0.14

gMVP

0.048

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