Genetic Variant NM_001042517.2:c.711A>T (chr13-60015973-T-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001042517.2(DIAPH3):c.711A>T(p.Lys237Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000923 in 1,613,254 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 14 hom. )

Consequence

DIAPH3
NM_001042517.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0600

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.003138423).

BP6

Variant 13-60015973-T-A is Benign according to our data. Variant chr13-60015973-T-A is described in ClinVar as Benign. ClinVar VariationId is 511180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00133 (203/152334) while in subpopulation EAS AF = 0.0319 (165/5176). AF 95% confidence interval is 0.0279. There are 2 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 203 AD,Unknown gene.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH3	NM_001042517.2	MANE Select	c.711A>T	p.Lys237Asn	missense	Exon 7 of 28	NP_001035982.1	Q9NSV4-3
DIAPH3	NM_001258366.2		c.678A>T	p.Lys226Asn	missense	Exon 6 of 27	NP_001245295.1	Q9NSV4-4
DIAPH3	NM_001258367.2		c.573A>T	p.Lys191Asn	missense	Exon 5 of 26	NP_001245296.1	Q9NSV4-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH3	ENST00000400324.9	TSL:1 MANE Select	c.711A>T	p.Lys237Asn	missense	Exon 7 of 28	ENSP00000383178.3	Q9NSV4-3
DIAPH3	ENST00000377908.6	TSL:1	c.678A>T	p.Lys226Asn	missense	Exon 6 of 27	ENSP00000367141.2	Q9NSV4-4
DIAPH3	ENST00000400320.5	TSL:1	c.573A>T	p.Lys191Asn	missense	Exon 5 of 26	ENSP00000383174.1	Q9NSV4-5

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.0318

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00229

AC:

569

AN:

248350

AF XY:

0.00213

show subpopulations

Gnomad AFR exome

AF:

0.000260

Gnomad AMR exome

AF:

0.0000872

Gnomad ASJ exome

AF:

0.00399

Gnomad EAS exome

AF:

0.0277

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.000880

AC:

1286

AN:

1460920

Hom.:

Cov.:

AF XY:

0.000835

AC XY:

607

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33454

American (AMR)

AF:

0.0000448

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00391

AC:

102

AN:

26110

East Asian (EAS)

AF:

0.0254

AC:

1006

AN:

39594

South Asian (SAS)

AF:

0.000371

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000990

AC:

AN:

1111518

Other (OTH)

AF:

0.00214

AC:

129

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00133

AC:

203

AN:

152334

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41576

American (AMR)

AF:

0.000457

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.0319

AC:

165

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00103

Hom.:

Bravo

AF:

0.00129

ESP6500AA

AF:

0.000276

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00224

AC:

270

Asia WGS

AF:

0.0100

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0031

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.7

PhyloP100

0.060

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.23

REVEL

Benign

0.17

Sift

Benign

0.48

Sift4G

Benign

0.46

Polyphen

0.0010

Vest4

0.14

MutPred

0.49

Loss of methylation at K237 (P = 0.0125)

MVP

0.79

MPC

0.15

ClinPred

0.014

GERP RS

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.050

gMVP

0.21

Mutation Taster

=100/0

polymorphism

(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