Genetic Variant NM_005219.5:c.1851_1853delTCC (chr5-141573996-TGGA-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_005219.5(DIAPH1):c.1851_1853delTCC(p.Pro618del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,280,532 control chromosomes in the GnomAD database, including 187 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 29 hom., cov: 28)

Exomes 𝑓: 0.033 ( 158 hom. )

Consequence

DIAPH1
NM_005219.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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: 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: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_005219.5

BP6

Variant 5-141573996-TGGA-T is Benign according to our data. Variant chr5-141573996-TGGA-T is described in ClinVar as Benign. ClinVar VariationId is 226563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0225 (2819/125344) while in subpopulation AFR AF = 0.0271 (893/32990). AF 95% confidence interval is 0.0256. There are 29 homozygotes in GnomAd4. There are 1298 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

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.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 28	NP_005210.3
DIAPH1	NM_001079812.3		c.1824_1826delTCC	p.Pro609del	disruptive_inframe_deletion	Exon 15 of 27	NP_001073280.1	O60610-3
DIAPH1	NM_001314007.2		c.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	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.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 28	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5	TSL:5	c.1824_1826delTCC	p.Pro609del	disruptive_inframe_deletion	Exon 15 of 27	ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1		c.1851_1853delTCC	p.Pro618del	disruptive_inframe_deletion	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes

AF:

0.0225

AC:

2813

AN:

125282

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0269

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0487

Gnomad EAS

AF:

0.000920

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00351

Gnomad MID

AF:

0.0398

Gnomad NFE

AF:

0.0237

Gnomad OTH

AF:

0.0197

GnomAD2 exomes

AF:

0.0722

AC:

6050

AN:

83800

AF XY:

0.0801

show subpopulations

Gnomad AFR exome

AF:

0.0450

Gnomad AMR exome

AF:

0.0327

Gnomad ASJ exome

AF:

0.130

Gnomad EAS exome

AF:

0.00828

Gnomad FIN exome

AF:

0.0753

Gnomad NFE exome

AF:

0.0829

Gnomad OTH exome

AF:

0.0628

GnomAD4 exome

AF:

0.0329

AC:

38061

AN:

1155188

Hom.:

158

AF XY:

0.0340

AC XY:

18958

AN XY:

557948

show subpopulations

African (AFR)

AF:

0.0355

AC:

915

AN:

25796

American (AMR)

AF:

0.0279

AC:

607

AN:

21772

Ashkenazi Jewish (ASJ)

AF:

0.0857

AC:

1585

AN:

18500

East Asian (EAS)

AF:

0.00925

AC:

225

AN:

24330

South Asian (SAS)

AF:

0.0401

AC:

1952

AN:

48668

European-Finnish (FIN)

AF:

0.0273

AC:

949

AN:

34790

Middle Eastern (MID)

AF:

0.0464

AC:

165

AN:

3554

European-Non Finnish (NFE)

AF:

0.0323

AC:

30082

AN:

932056

Other (OTH)

AF:

0.0346

AC:

1581

AN:

45722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

1636

3272

4909

6545

8181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1202

2404

3606

4808

6010

<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:

0.0225

AC:

2819

AN:

125344

Hom.:

Cov.:

AF XY:

0.0216

AC XY:

1298

AN XY:

60108

show subpopulations

African (AFR)

AF:

0.0271

AC:

893

AN:

32990

American (AMR)

AF:

0.0171

AC:

213

AN:

12422

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

150

AN:

3078

East Asian (EAS)

AF:

0.000923

AC:

AN:

4334

South Asian (SAS)

AF:

0.0109

AC:

AN:

3766

European-Finnish (FIN)

AF:

0.00351

AC:

AN:

7698

Middle Eastern (MID)

AF:

0.0385

AC:

AN:

208

European-Non Finnish (NFE)

AF:

0.0237

AC:

1384

AN:

58356

Other (OTH)

AF:

0.0190

AC:

AN:

1688

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0737

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Autosomal dominant nonsyndromic hearing loss 1 (2)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over