5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS1

The NM_005219.5(DIAPH1):c.1848_1853delTCCTCC(p.Pro617_Pro618del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000591 in 1,511,370 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00057 ( 1 hom. )

Consequence

DIAPH1
NM_005219.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 4.53

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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005219.5

BP6

Variant 5-141573996-TGGAGGA-T is Benign according to our data. Variant chr5-141573996-TGGAGGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 351294.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000876 (110/125546) while in subpopulation EAS AF = 0.00967 (42/4344). AF 95% confidence interval is 0.00735. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.1848_1853delTCCTCC	p.Pro617_Pro618del	disruptive_inframe_deletion	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_1853delTCCTCC	p.Pro617_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5 link	c.1821_1826delTCCTCC	p.Pro608_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	5		ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1 link	c.1848_1853delTCCTCC	p.Pro617_Pro618del	disruptive_inframe_deletion	Exon 16 of 29			ENSP00000494675.1	A0A2R8Y5N1
DIAPH1	ENST00000647330.1 link	n.1075_1080delTCCTCC		downstream_gene_variant				ENSP00000494308.1	A0A2R8YEF8

Frequencies

GnomAD3 genomes

AF:

0.000885

AC:

111

AN:

125476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000805

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00965

Gnomad SAS

AF:

0.00371

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00442

Gnomad NFE

AF:

0.000240

Gnomad OTH

AF:

0.00179

GnomAD2 exomes

AF:

0.00248

AC:

208

AN:

83800

AF XY:

0.00241

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.000720

Gnomad ASJ exome

AF:

0.000405

Gnomad EAS exome

AF:

0.0177

Gnomad FIN exome

AF:

0.000596

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.00218

GnomAD4 exome

AF:

0.000565

AC:

783

AN:

1385824

Hom.:

AF XY:

0.000623

AC XY:

426

AN XY:

683432

show subpopulations

African (AFR)

AF:

0.000669

AC:

AN:

31378

American (AMR)

AF:

0.000312

AC:

AN:

35288

Ashkenazi Jewish (ASJ)

AF:

0.000284

AC:

AN:

24690

East Asian (EAS)

AF:

0.00701

AC:

248

AN:

35358

South Asian (SAS)

AF:

0.00263

AC:

205

AN:

77824

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

47492

Middle Eastern (MID)

AF:

0.000451

AC:

AN:

4438

European-Non Finnish (NFE)

AF:

0.000202

AC:

217

AN:

1071924

Other (OTH)

AF:

0.00111

AC:

AN:

57432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

144

192

240

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:

0.000876

AC:

110

AN:

125546

Hom.:

Cov.:

AF XY:

0.000946

AC XY:

AN XY:

60230

show subpopulations

African (AFR)

AF:

0.000817

AC:

AN:

33034

American (AMR)

AF:

0.000804

AC:

AN:

12438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3076

East Asian (EAS)

AF:

0.00967

AC:

AN:

4344

South Asian (SAS)

AF:

0.00372

AC:

AN:

3766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.000240

AC:

AN:

58420

Other (OTH)

AF:

0.00177

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000430

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DIAPH1: BS1, BS2 -

Nonsyndromic Hearing Loss, Mixed

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Pro619_Pro620del in exon 16 of DIAPH1: This variant is not expected to have cl inical significance because it has been identified in 2.77% (14/506) of East Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs760344729). -

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

Benign:1

Jan 22, 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

4.5

Mutation Taster

=190/10

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