13-59666357-CAAAAAA-CAA

Variant names:

• chr13-59666357-CAAAA-C
• rs11421911
• NM_001042517.2:c.*223_*226delTTTT

Variant summary

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

The NM_001042517.2(DIAPH3):​c.*223_*226delTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 300,498 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: 0.0062 (0 hom.)
• Consequence: DIAPH3 NM_001042517.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.247
• 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.*223_*226delTTTT		3_prime_UTR	Exon 28 of 28	NP_001035982.1	Q9NSV4-3
	DIAPH3	NM_001258366.2		c.*223_*226delTTTT		3_prime_UTR	Exon 27 of 27	NP_001245295.1	Q9NSV4-4
	DIAPH3	NM_001258367.2		c.*223_*226delTTTT		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.*223_*226delTTTT		3_prime_UTR	Exon 28 of 28	ENSP00000383178.3	Q9NSV4-3
	DIAPH3	ENST00000649952.1		n.669_672delTTTT		non_coding_transcript_exon	Exon 2 of 2
	DIAPH3	ENST00000377908.6	TSL:1	c.*223_*226delTTTT		downstream_gene	N/A	ENSP00000367141.2	Q9NSV4-4

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111932 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000181

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00618 AC: 1165 AN: 188566 Hom.: 0 AF XY: 0.00620 AC XY: 616 AN XY: 99286

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

African (AFR) AF: 0.00611 AC: 28 AN: 4584

American (AMR) AF: 0.00596 AC: 39 AN: 6546

Ashkenazi Jewish (ASJ) AF: 0.00637 AC: 38 AN: 5962

East Asian (EAS) AF: 0.00586 AC: 65 AN: 11090

South Asian (SAS) AF: 0.00565 AC: 99 AN: 17514

European-Finnish (FIN) AF: 0.00505 AC: 45 AN: 8904

Middle Eastern (MID) AF: 0.00763 AC: 7 AN: 918

European-Non Finnish (NFE) AF: 0.00635 AC: 774 AN: 121874

Other (OTH) AF: 0.00626 AC: 70 AN: 11174

⚠️ 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: 0.00000893 AC: 1 AN: 111932 Hom.: 0 Cov.: 0 AF XY: 0.0000190 AC XY: 1 AN XY: 52650

⚠️ 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: 29000

American (AMR) AF: 0.00 AC: 0 AN: 10802

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3686

South Asian (SAS) AF: 0.00 AC: 0 AN: 3360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 226

European-Non Finnish (NFE) AF: 0.0000181 AC: 1 AN: 55110

Other (OTH) AF: 0.00 AC: 0 AN: 1494

⚠️ 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		-0.25

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;