13-59666357-CAAAAAA-CAAA

Variant names:

• chr13-59666357-CAAA-C
• rs11421911
• NM_001042517.2:c.*224_*226delTTT

Variant summary

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

The NM_001042517.2(DIAPH3):​c.*224_*226delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 297,640 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), 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 0.0000089 (0 hom., cov: 0)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: DIAPH3 NM_001042517.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.578
• 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.*224_*226delTTT		3_prime_UTR	Exon 28 of 28	NP_001035982.1	Q9NSV4-3
	DIAPH3	NM_001258366.2		c.*224_*226delTTT		3_prime_UTR	Exon 27 of 27	NP_001245295.1	Q9NSV4-4
	DIAPH3	NM_001258367.2		c.*224_*226delTTT		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.*224_*226delTTT		3_prime_UTR	Exon 28 of 28	ENSP00000383178.3	Q9NSV4-3
	DIAPH3	ENST00000649952.1		n.670_672delTTT		non_coding_transcript_exon	Exon 2 of 2
	DIAPH3	ENST00000377908.6	TSL:1	c.*224_*226delTTT		downstream_gene	N/A	ENSP00000367141.2	Q9NSV4-4

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111926 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000219

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0256 AC: 4762 AN: 185732 Hom.: 0 AF XY: 0.0261 AC XY: 2555 AN XY: 97822

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

African (AFR) AF: 0.0258 AC: 117 AN: 4530

American (AMR) AF: 0.0227 AC: 146 AN: 6424

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 149 AN: 5882

East Asian (EAS) AF: 0.0255 AC: 279 AN: 10928

South Asian (SAS) AF: 0.0278 AC: 479 AN: 17210

European-Finnish (FIN) AF: 0.0238 AC: 208 AN: 8752

Middle Eastern (MID) AF: 0.0280 AC: 25 AN: 892

European-Non Finnish (NFE) AF: 0.0256 AC: 3074 AN: 120086

Other (OTH) AF: 0.0258 AC: 285 AN: 11028

⚠️ 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: 0.00000894 AC: 1 AN: 111908 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 52660

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

African (AFR) AF: 0.00 AC: 0 AN: 29040

American (AMR) AF: 0.00 AC: 0 AN: 10804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2868

East Asian (EAS) AF: 0.00 AC: 0 AN: 3668

South Asian (SAS) AF: 0.00 AC: 0 AN: 3336

European-Finnish (FIN) AF: 0.000219 AC: 1 AN: 4560

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 55094

Other (OTH) AF: 0.00 AC: 0 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

dbSNP: rs11421911; hg19: chr13-60240491;