NM_005219.5:c.1845_1853dupTCCTCCTCC

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.1845_1853dupTCCTCCTCC(p.Pro616_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 0.0012 in 125,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 28)

Exomes 𝑓: 0.00075 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

DIAPH1
NM_005219.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005219.5

BP6

Variant 5-141573996-T-TGGAGGAGGA is Benign according to our data. Variant chr5-141573996-T-TGGAGGAGGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542361.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0012 (151/125544) while in subpopulation AMR AF = 0.0037 (46/12438). AF 95% confidence interval is 0.00285. There are 0 homozygotes in GnomAd4. There are 78 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.1845_1853dupTCCTCCTCC	p.Pro616_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.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5 link	c.1818_1826dupTCCTCCTCC	p.Pro607_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	5		ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1 link	c.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29			ENSP00000494675.1	A0A2R8Y5N1
DIAPH1	ENST00000647330.1 link	n.1072_1080dupTCCTCCTCC		downstream_gene_variant				ENSP00000494308.1	A0A2R8YEF8

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

150

AN:

125474

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000425

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00370

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00161

Gnomad SAS

AF:

0.00212

Gnomad FIN

AF:

0.00232

Gnomad MID

AF:

0.00442

Gnomad NFE

AF:

0.000924

Gnomad OTH

AF:

0.00119

GnomAD2 exomes

AF:

0.00160

AC:

134

AN:

83800

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.000620

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00478

Gnomad FIN exome

AF:

0.00119

Gnomad NFE exome

AF:

0.000884

Gnomad OTH exome

AF:

0.000436

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000752

AC:

1042

AN:

1386248

Hom.:

Cov.:

AF XY:

0.000772

AC XY:

528

AN XY:

683600

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000669

AC:

AN:

31388

American (AMR)

AF:

0.00108

AC:

AN:

35300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24734

East Asian (EAS)

AF:

0.000905

AC:

AN:

35356

South Asian (SAS)

AF:

0.00146

AC:

114

AN:

77848

European-Finnish (FIN)

AF:

0.00240

AC:

114

AN:

47502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4444

European-Non Finnish (NFE)

AF:

0.000638

AC:

684

AN:

1072232

Other (OTH)

AF:

0.000679

AC:

AN:

57444

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.363

Heterozygous variant carriers

147

196

245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.00120

AC:

151

AN:

125544

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

60228

show subpopulations

African (AFR)

AF:

0.000454

AC:

AN:

33034

American (AMR)

AF:

0.00370

AC:

AN:

12438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3078

East Asian (EAS)

AF:

0.00161

AC:

AN:

4344

South Asian (SAS)

AF:

0.00212

AC:

AN:

3766

European-Finnish (FIN)

AF:

0.00232

AC:

AN:

7764

Middle Eastern (MID)

AF:

0.00481

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.000924

AC:

AN:

58416

Other (OTH)

AF:

0.00118

AC:

AN:

1692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.000665

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Uncertain:1

Nov 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1845_1853dupTCCTCCTCC, results in the insertion of 3 amino acids to the DIAPH1 protein (p.Pro618_Pro620dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DIAPH1-related disease.¬¨‚Ä†ClinVar contains an entry for this variant (Variation ID:¬¨‚Ä†542361). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Benign:1

Oct 26, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DIAPH1-related disorder

Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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