5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGA

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_005219.5(DIAPH1):c.1842_1853delTCCTCCTCCTCC(p.Pro615_Pro618del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00047 in 1,511,804 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P614P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B: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 -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005219.5

BP6

Variant 5-141573996-TGGAGGAGGAGGA-T is Benign according to our data. Variant chr5-141573996-TGGAGGAGGAGGA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542370.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.1842_1853delTCCTCCTCCTCC	p.Pro615_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.1842_1853delTCCTCCTCCTCC	p.Pro615_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5 link	c.1815_1826delTCCTCCTCCTCC	p.Pro606_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	5		ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1 link	c.1842_1853delTCCTCCTCCTCC	p.Pro615_Pro618del	disruptive_inframe_deletion	Exon 16 of 29			ENSP00000494675.1	A0A2R8Y5N1
DIAPH1	ENST00000647330.1 link	n.1069_1080delTCCTCCTCCTCC		downstream_gene_variant				ENSP00000494308.1	A0A2R8YEF8

Frequencies

GnomAD3 genomes

AF:

0.000550

AC:

AN:

125476

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000455

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000805

Gnomad ASJ

AF:

0.000325

Gnomad EAS

AF:

0.000230

Gnomad SAS

AF:

0.000265

Gnomad FIN

AF:

0.000129

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000821

Gnomad OTH

AF:

0.000596

GnomAD4 exome

AF:

0.000463

AC:

642

AN:

1386328

Hom.:

AF XY:

0.000489

AC XY:

334

AN XY:

683644

show subpopulations

African (AFR)

AF:

0.000223

AC:

AN:

31388

American (AMR)

AF:

0.000142

AC:

AN:

35304

Ashkenazi Jewish (ASJ)

AF:

0.0000809

AC:

AN:

24734

East Asian (EAS)

AF:

0.000905

AC:

AN:

35360

South Asian (SAS)

AF:

0.000257

AC:

AN:

77860

European-Finnish (FIN)

AF:

0.000147

AC:

AN:

47516

Middle Eastern (MID)

AF:

0.000450

AC:

AN:

4444

European-Non Finnish (NFE)

AF:

0.000507

AC:

544

AN:

1072270

Other (OTH)

AF:

0.000400

AC:

AN:

57452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

126

157

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:

0.000550

AC:

AN:

125476

Hom.:

Cov.:

AF XY:

0.000615

AC XY:

AN XY:

60150

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

32940

American (AMR)

AF:

0.0000805

AC:

AN:

12420

Ashkenazi Jewish (ASJ)

AF:

0.000325

AC:

AN:

3078

East Asian (EAS)

AF:

0.000230

AC:

AN:

4354

South Asian (SAS)

AF:

0.000265

AC:

AN:

3778

European-Finnish (FIN)

AF:

0.000129

AC:

AN:

7764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.000821

AC:

AN:

58434

Other (OTH)

AF:

0.000596

AC:

AN:

1678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000587

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

May 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 20, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:2

Apr 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DIAPH1-related disorder

Uncertain:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DIAPH1 c.1842_1853del12 variant is predicted to result in an in-frame deletion (p.Pro617_Pro620del). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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

=175/25

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