5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_005219.5(DIAPH1):c.1848_1853dupTCCTCC(p.Pro617_Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 1,511,212 control chromosomes in the GnomAD database, including 190 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.024 ( 42 hom., cov: 28)

Exomes 𝑓: 0.025 ( 148 hom. )

Consequence

DIAPH1
NM_005219.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.13

Publications

2 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005219.5

BP6

Variant 5-141573996-T-TGGAGGA is Benign according to our data. Variant chr5-141573996-T-TGGAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475698.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 = 0.0239 (2998/125512) while in subpopulation EAS AF = 0.044 (191/4344). AF 95% confidence interval is 0.0389. There are 42 homozygotes in GnomAd4. There are 1440 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.1848_1853dupTCCTCC	p.Pro617_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	ENST00000389054.8	NP_005210.3	O60610-1Q6URC4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DIAPH1	ENST00000389054.8 link	c.1848_1853dupTCCTCC	p.Pro617_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5 link	c.1821_1826dupTCCTCC	p.Pro608_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	5		ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1 link	c.1848_1853dupTCCTCC	p.Pro617_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29			ENSP00000494675.1	A0A2R8Y5N1
DIAPH1	ENST00000647330.1 link	n.1075_1080dupTCCTCC		downstream_gene_variant				ENSP00000494308.1	A0A2R8YEF8

Frequencies

GnomAD3 genomes

AF:

0.0239

AC:

2999

AN:

125442

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0121

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00990

Gnomad ASJ

AF:

0.00682

Gnomad EAS

AF:

0.0441

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.0472

Gnomad MID

AF:

0.0310

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0131

GnomAD2 exomes

AF:

0.0287

AC:

2409

AN:

83800

AF XY:

0.0290

show subpopulations

Gnomad AFR exome

AF:

0.0167

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.00546

Gnomad EAS exome

AF:

0.0811

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.0289

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0248

AC:

34385

AN:

1385700

Hom.:

148

Cov.:

AF XY:

0.0246

AC XY:

16823

AN XY:

683356

show subpopulations

African (AFR)

AF:

0.0133

AC:

417

AN:

31384

American (AMR)

AF:

0.00737

AC:

260

AN:

35302

Ashkenazi Jewish (ASJ)

AF:

0.00505

AC:

125

AN:

24732

East Asian (EAS)

AF:

0.0442

AC:

1562

AN:

35350

South Asian (SAS)

AF:

0.0218

AC:

1697

AN:

77824

European-Finnish (FIN)

AF:

0.0419

AC:

1988

AN:

47426

Middle Eastern (MID)

AF:

0.00788

AC:

AN:

4444

European-Non Finnish (NFE)

AF:

0.0252

AC:

27017

AN:

1071796

Other (OTH)

AF:

0.0224

AC:

1284

AN:

57442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

1577

3153

4730

6306

7883

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1008

2016

3024

4032

5040

<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:

0.0239

AC:

2998

AN:

125512

Hom.:

Cov.:

AF XY:

0.0239

AC XY:

1440

AN XY:

60210

show subpopulations

African (AFR)

AF:

0.0122

AC:

404

AN:

33032

American (AMR)

AF:

0.00989

AC:

123

AN:

12434

Ashkenazi Jewish (ASJ)

AF:

0.00682

AC:

AN:

3078

East Asian (EAS)

AF:

0.0440

AC:

191

AN:

4344

South Asian (SAS)

AF:

0.0274

AC:

103

AN:

3762

European-Finnish (FIN)

AF:

0.0472

AC:

366

AN:

7754

Middle Eastern (MID)

AF:

0.0240

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0298

AC:

1741

AN:

58406

Other (OTH)

AF:

0.0130

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

125

250

374

499

624

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0118

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 07, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 28, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 08, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro608[15] in exon 16 of DIAPH1: This variant is not expected to have clinical significance because it has been identied in 1.2% (6/506) of East Asian chromos omes and 0.7% (51/7548) of European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs374236039). -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=77/23

polymorphism

(source)

Splicing

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