X-96738667-G-T

Variant names:

• chrX-96738667-G-T
• rs20374
• NM_006729.5:c.247G>T

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.247G>T​(p.Ala83Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A83T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: DIAPH2 NM_006729.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.148
• Publications: 4 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 Gene-Disease associations (from GenCC):

• premature ovarian failure 2A

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.069925964).

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>T	p.Ala83Ser	missense	Exon 3 of 27	NP_006720.1	O60879-1
	DIAPH2	NM_007309.4		c.247G>T	p.Ala83Ser	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>T	p.Ala83Ser	missense	Exon 3 of 27	ENSP00000321348.8	O60879-1
	DIAPH2	ENST00000373049.8	TSL:1	c.247G>T	p.Ala83Ser	missense	Exon 3 of 27	ENSP00000362140.4	O60879-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.84
DANN	Benign	0.45
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.15
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.13
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.015	B
Vest4		0.068
MutPred		0.31		Gain of disorder (P = 0.0435)
MVP		0.62
MPC		0.30
ClinPred		0.12	T
GERP RS		4.8
Varity_R		0.085
gMVP		0.27
Mutation Taster		=96/4	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: rs20374; hg19: chrX-95993666;