NM_006729.5:c.3265A>G

Variant names:

• chrX-97599276-A-G
• rs2071576335
• NM_006729.5:c.3265A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006729.5(DIAPH2):​c.3265A>G​(p.Arg1089Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,082,073 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: DIAPH2 NM_006729.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.69
• Publications: 0 publications found

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-AS1 (HGNC:16972): (DIAPH2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21035054).

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.3265A>G	p.Arg1089Gly	missense	Exon 27 of 27	NP_006720.1	O60879-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH2	ENST00000324765.13	TSL:1 MANE Select	c.3265A>G	p.Arg1089Gly	missense	Exon 27 of 27	ENSP00000321348.8	O60879-1
	DIAPH2-AS1	ENST00000445414.2	TSL:2	n.397+3535T>C		intron	N/A
	DIAPH2-AS1	ENST00000744263.1		n.398+3535T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000277 AC: 3 AN: 1082073 Hom.: 0 Cov.: 24 AF XY: 0.00000286 AC XY: 1 AN XY: 349675

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25973

American (AMR) AF: 0.00 AC: 0 AN: 34585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18986

East Asian (EAS) AF: 0.00 AC: 0 AN: 29619

South Asian (SAS) AF: 0.00 AC: 0 AN: 52644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.00000361 AC: 3 AN: 831297

Other (OTH) AF: 0.00 AC: 0 AN: 45281

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.44
Sift	Benign	0.048	D
Sift4G	Benign	0.14	T
Polyphen		0.82	P
Vest4		0.32
MutPred		0.26		Loss of MoRF binding (P = 0.1028)
MVP		0.87
MPC		1.1
ClinPred		0.45	T
GERP RS		4.0
Varity_R		0.13
gMVP		0.47
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs2071576335; hg19: chrX-96854275; COSMIC: COSV105200736; COSMIC: COSV105200736;