X-96738667-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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 (★★). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.148

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]

ACMG classification

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 GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH2	NM_006729.5	c.247G>A	p.Ala83Thr	missense_variant	3/27	ENST00000324765.13
DIAPH2	NM_007309.4	c.247G>A	p.Ala83Thr	missense_variant	3/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH2	ENST00000324765.13	c.247G>A	p.Ala83Thr	missense_variant	3/27	1	NM_006729.5	A2
DIAPH2	ENST00000373049.8	c.247G>A	p.Ala83Thr	missense_variant	3/27	1		P3

Frequencies

GnomAD3 genomes AF: 0.00634 AC: 705 AN: 111135 Hom.: 4 Cov.: 22 AF XY: 0.00512 AC XY: 171 AN XY: 33395

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.: 4 AF XY: 0.00577 AC XY: 376 AN XY: 65186

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.: 41 Cov.: 28 AF XY: 0.00830 AC XY: 2987 AN XY: 359730

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.: 4 Cov.: 22 AF XY: 0.00511 AC XY: 171 AN XY: 33454

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: 43

ALSPAC AF: 0.0125 AC: 36

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.0107 AC: 72

ExAC AF: 0.00680 AC: 826

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	5.0
Dann	Uncertain	0.98
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.66	T;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
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	T
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

Other links and lift over

dbSNP: rs20374; hg19: chrX-95993666;