NM_001042517.2:c.*224_*226dupTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001042517.2(DIAPH3):​c.*224_*226dupTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00075 (0 hom.)
• Consequence: DIAPH3 NM_001042517.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 13-59666357-C-CAAA is Benign according to our data. Variant chr13-59666357-C-CAAA is described in ClinVar as Likely_benign. ClinVar VariationId is 1178019.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 332 AD,Unknown gene.

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_*226dupTTT		3_prime_UTR	Exon 28 of 28	NP_001035982.1	Q9NSV4-3
	DIAPH3	NM_001258366.2		c.*224_*226dupTTT		3_prime_UTR	Exon 27 of 27	NP_001245295.1	Q9NSV4-4
	DIAPH3	NM_001258367.2		c.*224_*226dupTTT		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_*226dupTTT		3_prime_UTR	Exon 28 of 28	ENSP00000383178.3	Q9NSV4-3
	DIAPH3	ENST00000649952.1		n.670_672dupTTT		non_coding_transcript_exon	Exon 2 of 2
	DIAPH3	ENST00000377908.6	TSL:1	c.*224_*226dupTTT		downstream_gene	N/A	ENSP00000367141.2	Q9NSV4-4

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 334 AN: 111908 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000595

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000109

Gnomad OTH AF: 0.00201

GnomAD4 exome AF: 0.000747 AC: 142 AN: 190106 Hom.: 0 Cov.: 0 AF XY: 0.000729 AC XY: 73 AN XY: 100090

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

African (AFR) AF: 0.00346 AC: 16 AN: 4620

American (AMR) AF: 0.000906 AC: 6 AN: 6622

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 7 AN: 6006

East Asian (EAS) AF: 0.000715 AC: 8 AN: 11190

South Asian (SAS) AF: 0.00102 AC: 18 AN: 17674

European-Finnish (FIN) AF: 0.000557 AC: 5 AN: 8970

Middle Eastern (MID) AF: 0.00108 AC: 1 AN: 922

European-Non Finnish (NFE) AF: 0.000586 AC: 72 AN: 122830

Other (OTH) AF: 0.000798 AC: 9 AN: 11272

⚠️ 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: 0.00297 AC: 332 AN: 111890 Hom.: 2 Cov.: 0 AF XY: 0.00287 AC XY: 151 AN XY: 52662

African (AFR) AF: 0.0107 AC: 310 AN: 29028

American (AMR) AF: 0.00102 AC: 11 AN: 10802

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

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

South Asian (SAS) AF: 0.000600 AC: 2 AN: 3336

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

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

European-Non Finnish (NFE) AF: 0.000109 AC: 6 AN: 55090

Other (OTH) AF: 0.00199 AC: 3 AN: 1506

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11421911;

hg19: chr13-60240491;