5-141576268-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005219.5(DIAPH1):c.1423G>A(p.Glu475Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000877 in 1,614,028 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 2 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 5.60

Publications

6 publications found

Variant links:

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 Gene-Disease associations (from GenCC):

DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

DIAPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0089969635).

BP6

Variant 5-141576268-C-T is Benign according to our data. Variant chr5-141576268-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 351296.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.1423G>A	p.Glu475Lys	missense_variant	Exon 14 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DIAPH1	ENST00000389054.8 link	c.1423G>A	p.Glu475Lys	missense_variant	Exon 14 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5 link	c.1396G>A	p.Glu466Lys	missense_variant	Exon 13 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1 link	c.1423G>A	p.Glu475Lys	missense_variant	Exon 14 of 29			ENSP00000494675.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00810

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00119

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00122

AC:

305

AN:

249502

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00835

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000850

AC:

1242

AN:

1461670

Hom.:

Cov.:

AF XY:

0.000838

AC XY:

609

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00811

AC:

433

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000696

AC:

774

AN:

1111828

Other (OTH)

AF:

0.000414

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

126

189

252

315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00114

AC:

173

AN:

152358

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41586

American (AMR)

AF:

0.000196

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00810

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00119

AC:

AN:

68042

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000712

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000731

AC:

ExAC

AF:

0.00108

AC:

131

EpiCase

AF:

0.000709

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 31, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DIAPH1: BS1 -

Jan 25, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 03, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu475Lys in exon 14 of DIAPH1: This variant is not expected to have clinical significance because it has been identified in 0.8% (216/25792) of Finnish chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs193036129). -

Autosomal dominant nonsyndromic hearing loss 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.;T;.;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.0090

T;T;T;T;T;T

MetaSVM

Uncertain

-0.021

MutationAssessor

Benign

1.9

L;.;.;.;.;.

PhyloP100

5.6

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.1

D;.;.;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.074

T;.;.;T;T;T

Sift4G

Benign

0.20

T;.;T;T;T;T

Polyphen

0.99

D;.;.;.;.;.

Vest4

0.39

MVP

0.84

MPC

0.13

ClinPred

0.58

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.27

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over