13-59666357-CAAAAAA-CAAAAA

Variant names:

• chr13-59666357-CA-C
• rs11421911
• NM_001042517.2:c.*226delT

Variant summary

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

The NM_001042517.2(DIAPH3):​c.*226delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.0013 (0 hom., cov: 0)
  • Exomes 𝑓: 0.18 (0 hom.)
• Consequence: DIAPH3 NM_001042517.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.612
• Publications: 0 publications found

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 nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• auditory neuropathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• autosomal dominant auditory neuropathy 1

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042517.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH3	NM_001042517.2	MANE Select	c.*226delT		3_prime_UTR	Exon 28 of 28	NP_001035982.1	Q9NSV4-3
	DIAPH3	NM_001258366.2		c.*226delT		3_prime_UTR	Exon 27 of 27	NP_001245295.1	Q9NSV4-4
	DIAPH3	NM_001258367.2		c.*226delT		3_prime_UTR	Exon 26 of 26	NP_001245296.1	Q9NSV4-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH3	ENST00000400324.9	TSL:1 MANE Select	c.*226delT		3_prime_UTR	Exon 28 of 28	ENSP00000383178.3	Q9NSV4-3
	DIAPH3	ENST00000649952.1		n.672delT		non_coding_transcript_exon	Exon 2 of 2
	DIAPH3	ENST00000377908.6	TSL:1	c.*226delT		downstream_gene	N/A	ENSP00000367141.2	Q9NSV4-4

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 144 AN: 111916 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000463

Gnomad ASJ AF: 0.000349

Gnomad EAS AF: 0.00109

Gnomad SAS AF: 0.00179

Gnomad FIN AF: 0.00176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00134

GnomAD4 exome AF: 0.177 AC: 32944 AN: 186470 Hom.: 0 Cov.: 0 AF XY: 0.178 AC XY: 17455 AN XY: 98262

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

African (AFR) AF: 0.168 AC: 767 AN: 4558

American (AMR) AF: 0.181 AC: 1166 AN: 6452

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 1089 AN: 5892

East Asian (EAS) AF: 0.191 AC: 2104 AN: 11012

South Asian (SAS) AF: 0.186 AC: 3228 AN: 17356

European-Finnish (FIN) AF: 0.169 AC: 1483 AN: 8794

Middle Eastern (MID) AF: 0.180 AC: 163 AN: 908

European-Non Finnish (NFE) AF: 0.174 AC: 20975 AN: 120424

Other (OTH) AF: 0.178 AC: 1969 AN: 11074

⚠️ 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.

GnomAD4 genome AF: 0.00129 AC: 144 AN: 111898 Hom.: 0 Cov.: 0 AF XY: 0.00148 AC XY: 78 AN XY: 52652

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

African (AFR) AF: 0.00162 AC: 47 AN: 29040

American (AMR) AF: 0.000463 AC: 5 AN: 10800

Ashkenazi Jewish (ASJ) AF: 0.000349 AC: 1 AN: 2868

East Asian (EAS) AF: 0.00109 AC: 4 AN: 3668

South Asian (SAS) AF: 0.00180 AC: 6 AN: 3336

European-Finnish (FIN) AF: 0.00176 AC: 8 AN: 4558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 206

European-Non Finnish (NFE) AF: 0.00129 AC: 71 AN: 55090

Other (OTH) AF: 0.00133 AC: 2 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11421911; hg19: chr13-60240491;