Genetic Variant NM_001042517.2:c.*225_*226dupTT (chr13-59666357-C-CAA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_001042517.2(DIAPH3):c.*225_*226dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.044 ( 242 hom., cov: 0)

Exomes 𝑓: 0.017 ( 0 hom. )

Consequence

DIAPH3
NM_001042517.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.612

Publications

0 publications found

Variant links:

Genes affected

DIAPH3 (HGNC:15480): (diaphanous related formin 3) This gene encodes a member of the diaphanous subfamily of the formin family. Members of this family are involved in actin remodeling and regulate cell movement and adhesion. Mutations in this gene are associated with autosomal dominant auditory neuropathy 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

DIAPH3 Gene-Disease associations (from GenCC):

autosomal dominant auditory neuropathy 1
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
auditory neuropathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

DIAPH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 13-59666357-C-CAA is Benign according to our data. Variant chr13-59666357-C-CAA is described in ClinVar as [Benign]. Clinvar id is 1225244.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH3	NM_001042517.2 link	c.225_226dupTT		3_prime_UTR_variant	Exon 28 of 28	ENST00000400324.9	NP_001035982.1	Q9NSV4-3B4DPV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH3	ENST00000400324.9 link	c.225_226dupTT		3_prime_UTR_variant	Exon 28 of 28	1	NM_001042517.2	ENSP00000383178.3		Q9NSV4-3
DIAPH3	ENST00000400319.5 link	c.225_226dupTT		downstream_gene_variant		1		ENSP00000383173.1		Q9NSV4-6

Frequencies

GnomAD3 genomes

AF:

0.0442

AC:

4945

AN:

111828

Hom.:

240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.00364

Gnomad AMR

AF:

0.0247

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.0402

Gnomad SAS

AF:

0.0429

Gnomad FIN

AF:

0.00351

Gnomad MID

AF:

0.0221

Gnomad NFE

AF:

0.00835

Gnomad OTH

AF:

0.0475

GnomAD4 exome

AF:

0.0172

AC:

3247

AN:

189210

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1725

AN XY:

99628

show subpopulations

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

African (AFR)

AF:

0.0438

AC:

201

AN:

4586

American (AMR)

AF:

0.0158

AC:

104

AN:

6598

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

136

AN:

5974

East Asian (EAS)

AF:

0.0172

AC:

192

AN:

11146

South Asian (SAS)

AF:

0.0242

AC:

425

AN:

17582

European-Finnish (FIN)

AF:

0.0121

AC:

108

AN:

8940

Middle Eastern (MID)

AF:

0.0239

AC:

AN:

922

European-Non Finnish (NFE)

AF:

0.0152

AC:

1861

AN:

122242

Other (OTH)

AF:

0.0176

AC:

198

AN:

11220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.307

Heterozygous variant carriers

284

569

853

1138

1422

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0443

AC:

4952

AN:

111808

Hom.:

242

Cov.:

AF XY:

0.0443

AC XY:

2332

AN XY:

52624

show subpopulations

African (AFR)

AF:

0.129

AC:

3737

AN:

28986

American (AMR)

AF:

0.0247

AC:

267

AN:

10796

Ashkenazi Jewish (ASJ)

AF:

0.0363

AC:

104

AN:

2866

East Asian (EAS)

AF:

0.0398

AC:

146

AN:

3664

South Asian (SAS)

AF:

0.0429

AC:

143

AN:

3336

European-Finnish (FIN)

AF:

0.00351

AC:

AN:

4558

Middle Eastern (MID)

AF:

0.0243

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.00835

AC:

460

AN:

55066

Other (OTH)

AF:

0.0471

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

195

390

586

781

976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 13, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001042517.2:c.225_226dupTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over