rs368350070

Variant names:

• chrX-97599282-C-T
• rs368350070
• NM_006729.5:c.3271C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006729.5(DIAPH2):​c.3271C>T​(p.Arg1091Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000176 in 1,193,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000019 (0 hom. 8 hem.)
• Consequence: DIAPH2 NM_006729.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.28
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3342104).
• BS2: High Hemizygotes in GnomAdExome4 at 8 Unknown gene

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.3271C>T	p.Arg1091Cys	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.3271C>T	p.Arg1091Cys	missense	Exon 27 of 27	ENSP00000321348.8	O60879-1
	DIAPH2-AS1	ENST00000445414.2	TSL:2	n.397+3529G>A		intron	N/A
	DIAPH2-AS1	ENST00000744263.1		n.398+3529G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112222 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000467 AC: 8 AN: 171181 AF XY: 0.0000351

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000533

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 20 AN: 1080980 Hom.: 0 Cov.: 24 AF XY: 0.0000229 AC XY: 8 AN XY: 348924

African (AFR) AF: 0.00 AC: 0 AN: 25951

American (AMR) AF: 0.00 AC: 0 AN: 34562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18961

East Asian (EAS) AF: 0.000203 AC: 6 AN: 29522

South Asian (SAS) AF: 0.00 AC: 0 AN: 52643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.0000157 AC: 13 AN: 830528

Other (OTH) AF: 0.0000221 AC: 1 AN: 45211

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112222 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34394

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

African (AFR) AF: 0.00 AC: 0 AN: 30886

American (AMR) AF: 0.00 AC: 0 AN: 10562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.00 AC: 0 AN: 2726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6109

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53250

Other (OTH) AF: 0.00 AC: 0 AN: 1520

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000412 AC: 5

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	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.34	N
PhyloP100		5.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.31	N
REVEL	Uncertain	0.58
Sift	Benign	0.039	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.80
MPC		1.2
ClinPred		0.29	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.44
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368350070; hg19: chrX-96854281; COSMIC: COSV61292514; COSMIC: COSV61292514;