13-60015973-T-A

Position:

chr13-60015973-T-A

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 (HGNC:):

DIAPH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH3	NM_001042517.2 linkuse as main transcript	c.711A>T	p.Lys237Asn	missense_variant	7/28	ENST00000400324.9	NP_001035982.1	Q9NSV4-3B4DPV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH3	ENST00000400324.9 linkuse as main transcript	c.711A>T	p.Lys237Asn	missense_variant	7/28	1	NM_001042517.2	ENSP00000383178.3		Q9NSV4-3
DIAPH3	ENST00000400319.5 linkuse as main transcript	c.501A>T	p.Lys167Asn	missense_variant	5/26	1		ENSP00000383173.1		Q9NSV4-6

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

GnomAD3 exomes

AF:

0.00229

AC:

569

AN:

248350

Hom.:

AF XY:

0.00213

AC XY:

287

AN XY:

134754

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 SAS exome

AF:

0.000328

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

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00391

Gnomad4 EAS exome

AF:

0.0254

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00214

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152334

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.0319

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	This variant is associated with the following publications: (PMID: 23562982) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;.;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.67

T;T;T;T;T

MetaRNN

Benign

0.0031

T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.7

L;.;.;.;L

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.23

N;N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.48

T;T;T;T;T

Sift4G

Benign

0.46

T;T;T;T;T

Polyphen

0.0010

B;.;.;.;.

Vest4

0.14

MutPred

0.49

Loss of methylation at K237 (P = 0.0125);.;.;.;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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over