Genetic Variant NM_001042517.2:c.*225_*226delTT (chr13-59666357-CAA-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001042517.2(DIAPH3):c.*225_*226delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0472 in 293,908 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.076 ( 0 hom. )

Consequence

DIAPH3
NM_001042517.2 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.578

Publications

0 publications found

Variant links:

Genes affected

DIAPH3 (HGNC:15480): (diaphanous related formin 3) This gene encodes a member of the diaphanous subfamily of the formin family. Members of this family are involved in actin remodeling and regulate cell movement and adhesion. Mutations in this gene are associated with autosomal dominant auditory neuropathy 1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

DIAPH3 Gene-Disease associations (from GenCC):

autosomal dominant auditory neuropathy 1
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
auditory neuropathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

DIAPH3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH3	NM_001042517.2 link	c.225_226delTT		3_prime_UTR_variant	Exon 28 of 28	ENST00000400324.9	NP_001035982.1	Q9NSV4-3B4DPV3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH3	ENST00000400324.9 link	c.225_226delTT		3_prime_UTR_variant	Exon 28 of 28	1	NM_001042517.2	ENSP00000383178.3		Q9NSV4-3
DIAPH3	ENST00000400319.5 link	c.225_226delTT		downstream_gene_variant		1		ENSP00000383173.1		Q9NSV4-6

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

111904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000926

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00110

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000907

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0762

AC:

13865

AN:

182022

Hom.:

AF XY:

0.0754

AC XY:

7235

AN XY:

95908

show subpopulations

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

African (AFR)

AF:

0.0757

AC:

335

AN:

4426

American (AMR)

AF:

0.0850

AC:

528

AN:

6214

Ashkenazi Jewish (ASJ)

AF:

0.0725

AC:

419

AN:

5780

East Asian (EAS)

AF:

0.0810

AC:

868

AN:

10720

South Asian (SAS)

AF:

0.0790

AC:

1334

AN:

16876

European-Finnish (FIN)

AF:

0.0722

AC:

620

AN:

8582

Middle Eastern (MID)

AF:

0.0788

AC:

AN:

888

European-Non Finnish (NFE)

AF:

0.0752

AC:

8854

AN:

117774

Other (OTH)

AF:

0.0778

AC:

837

AN:

10762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.294

Heterozygous variant carriers

1176

2353

3529

4706

5882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000125

AC:

AN:

111886

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

52644

show subpopulations

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

African (AFR)

AF:

0.000103

AC:

AN:

29038

American (AMR)

AF:

0.0000926

AC:

AN:

10802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2864

East Asian (EAS)

AF:

0.00

AC:

AN:

3668

South Asian (SAS)

AF:

0.00

AC:

AN:

3336

European-Finnish (FIN)

AF:

0.00110

AC:

AN:

4552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.0000908

AC:

AN:

55092

Other (OTH)

AF:

0.00

AC:

AN:

1502

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000325), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.368

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.58

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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NM_001042517.2:c.225_226delTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over