chr5-141573996-T-TGGA

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_005219.5(DIAPH1):c.1851_1853dupTCC(p.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 0.0312 in 1,510,582 control chromosomes in the GnomAD database, including 343 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 0.046 ( 162 hom., cov: 28)

Exomes 𝑓: 0.030 ( 181 hom. )

Consequence

DIAPH1
NM_005219.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

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-TGGA is Benign according to our data. Variant chr5-141573996-T-TGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.1851_1853dupTCC	p.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.1851_1853dupTCC	p.Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5 link	c.1824_1826dupTCC	p.Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	5		ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1 link	c.1851_1853dupTCC	p.Pro618dup	disruptive_inframe_insertion	Exon 16 of 29			ENSP00000494675.1	A0A2R8Y5N1
DIAPH1	ENST00000647330.1 link	n.1078_1080dupTCC		downstream_gene_variant				ENSP00000494308.1	A0A2R8YEF8

Frequencies

GnomAD3 genomes

AF:

0.0457

AC:

5727

AN:

125396

Hom.:

162

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0908

Gnomad AMI

AF:

0.0835

Gnomad AMR

AF:

0.0300

Gnomad ASJ

AF:

0.0526

Gnomad EAS

AF:

0.0290

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.00618

Gnomad MID

AF:

0.0310

Gnomad NFE

AF:

0.0311

Gnomad OTH

AF:

0.0369

GnomAD2 exomes

AF:

0.0450

AC:

3773

AN:

83800

AF XY:

0.0457

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.0433

Gnomad ASJ exome

AF:

0.0676

Gnomad EAS exome

AF:

0.0539

Gnomad FIN exome

AF:

0.00691

Gnomad NFE exome

AF:

0.0407

Gnomad OTH exome

AF:

0.0536

GnomAD4 exome

AF:

0.0299

AC:

41374

AN:

1385114

Hom.:

181

Cov.:

AF XY:

0.0296

AC XY:

20243

AN XY:

683052

show subpopulations

African (AFR)

AF:

0.0799

AC:

2506

AN:

31376

American (AMR)

AF:

0.0248

AC:

876

AN:

35300

Ashkenazi Jewish (ASJ)

AF:

0.0467

AC:

1154

AN:

24720

East Asian (EAS)

AF:

0.0279

AC:

983

AN:

35294

South Asian (SAS)

AF:

0.0243

AC:

1891

AN:

77766

European-Finnish (FIN)

AF:

0.00671

AC:

318

AN:

47412

Middle Eastern (MID)

AF:

0.0331

AC:

147

AN:

4442

European-Non Finnish (NFE)

AF:

0.0294

AC:

31498

AN:

1071408

Other (OTH)

AF:

0.0349

AC:

2001

AN:

57396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

2185

4369

6554

8738

10923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1268

2536

3804

5072

6340

<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:

0.0457

AC:

5733

AN:

125468

Hom.:

162

Cov.:

AF XY:

0.0447

AC XY:

2693

AN XY:

60188

show subpopulations

African (AFR)

AF:

0.0907

AC:

2993

AN:

32994

American (AMR)

AF:

0.0300

AC:

373

AN:

12432

Ashkenazi Jewish (ASJ)

AF:

0.0526

AC:

162

AN:

3078

East Asian (EAS)

AF:

0.0291

AC:

126

AN:

4336

South Asian (SAS)

AF:

0.0205

AC:

AN:

3764

European-Finnish (FIN)

AF:

0.00618

AC:

AN:

7762

Middle Eastern (MID)

AF:

0.0288

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0311

AC:

1816

AN:

58400

Other (OTH)

AF:

0.0384

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

249

498

747

996

1245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0151

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 31, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.1821TCC[12] in exon 16 of DIAPH1: This allele is a part of a poly TCC stretch and is not expected to have clinical significance because it has been identified in 3.1% (238/7732) of European American chromosomes and 6.7% (239/3592) of Afri can American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS/; dbSNP rs35249032). -

Jan 16, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 24, 2017

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

Significance:Likely benign

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: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

=76/24

polymorphism (auto)

(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