Genetic Variant DIAPH3:c.627-28G>A (chr13-60016173-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042517.2(DIAPH3):c.627-28G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,602,014 control chromosomes in the GnomAD database, including 71,942 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5371 hom., cov: 33)

Exomes 𝑓: 0.29 ( 66571 hom. )

Consequence

DIAPH3
NM_001042517.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.913

Publications

3 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 links:

DIAPH3-AS1 (HGNC:39915): (DIAPH3 antisense RNA 1)

DIAPH3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 13-60016173-C-T is Benign according to our data. Variant chr13-60016173-C-T is described in ClinVar as Benign. ClinVar VariationId is 1272224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042517.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DIAPH3	NM_001042517.2	MANE Select	c.627-28G>A	intron	N/A	NP_001035982.1	Q9NSV4-3
DIAPH3	NM_001258366.2		c.594-28G>A	intron	N/A	NP_001245295.1	Q9NSV4-4
DIAPH3	NM_001258367.2		c.489-28G>A	intron	N/A	NP_001245296.1	Q9NSV4-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DIAPH3	ENST00000400324.9	TSL:1 MANE Select	c.627-28G>A	intron	N/A	ENSP00000383178.3	Q9NSV4-3
DIAPH3	ENST00000377908.6	TSL:1	c.594-28G>A	intron	N/A	ENSP00000367141.2	Q9NSV4-4
DIAPH3	ENST00000400320.5	TSL:1	c.489-28G>A	intron	N/A	ENSP00000383174.1	Q9NSV4-5

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36466

AN:

151994

Hom.:

5362

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0908

Gnomad AMI

AF:

0.302

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.263

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.301

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.251

GnomAD2 exomes

AF:

0.273

AC:

66472

AN:

243246

AF XY:

0.272

show subpopulations

Gnomad AFR exome

AF:

0.0853

Gnomad AMR exome

AF:

0.440

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.00130

Gnomad FIN exome

AF:

0.306

Gnomad NFE exome

AF:

0.303

Gnomad OTH exome

AF:

0.274

GnomAD4 exome

AF:

0.294

AC:

426470

AN:

1449902

Hom.:

66571

Cov.:

AF XY:

0.292

AC XY:

211012

AN XY:

721992

show subpopulations

African (AFR)

AF:

0.0842

AC:

2798

AN:

33238

American (AMR)

AF:

0.431

AC:

19145

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.260

AC:

6755

AN:

25952

East Asian (EAS)

AF:

0.00142

AC:

AN:

39498

South Asian (SAS)

AF:

0.216

AC:

18510

AN:

85812

European-Finnish (FIN)

AF:

0.299

AC:

15861

AN:

53102

Middle Eastern (MID)

AF:

0.212

AC:

1216

AN:

5744

European-Non Finnish (NFE)

AF:

0.314

AC:

345796

AN:

1102144

Other (OTH)

AF:

0.272

AC:

16333

AN:

59982

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

14836

29672

44508

59344

74180

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11076

22152

33228

44304

55380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.240

AC:

36483

AN:

152112

Hom.:

5371

Cov.:

AF XY:

0.240

AC XY:

17833

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.0908

AC:

3769

AN:

41520

American (AMR)

AF:

0.375

AC:

5724

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

912

AN:

3470

East Asian (EAS)

AF:

0.00367

AC:

AN:

5184

South Asian (SAS)

AF:

0.206

AC:

992

AN:

4824

European-Finnish (FIN)

AF:

0.301

AC:

3179

AN:

10554

Middle Eastern (MID)

AF:

0.240

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.309

AC:

21017

AN:

67970

Other (OTH)

AF:

0.249

AC:

527

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1338

2676

4013

5351

6689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.274

Hom.:

2213

Bravo

AF:

0.241

Asia WGS

AF:

0.104

AC:

363

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.45

(source)

DANN

Benign

0.61

PhyloP100

-0.91

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over