chr5-141573996-T-TGGAGGAGGA

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: Orphanet, ClinGen
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH1	NM_005219.5	MANE Select	c.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	NP_005210.3
DIAPH1	NM_001079812.3		c.1818_1826dupTCCTCCTCC	p.Pro607_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	NP_001073280.1	O60610-3
DIAPH1	NM_001314007.2		c.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5	TSL:5	c.1818_1826dupTCCTCCTCC	p.Pro607_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1		c.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

DIAPH1-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over