rs339536

Variant names:

• chr13-59977280-T-C
• rs339536
• NM_001042517.2:c.1546-2824A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001042517.2(DIAPH3):​c.1546-2824A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 151,632 control chromosomes in the GnomAD database, including 43,201 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43201 hom., cov: 31)
• Consequence: DIAPH3 NM_001042517.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• 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 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH3	NM_001042517.2	c.1546-2824A>G		intron_variant	Intron 14 of 27	ENST00000400324.9	NP_001035982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH3	ENST00000400324.9	c.1546-2824A>G		intron_variant	Intron 14 of 27	1	NM_001042517.2	ENSP00000383178.3
DIAPH3	ENST00000400319.5	c.1336-2824A>G		intron_variant	Intron 12 of 25	1		ENSP00000383173.1

Frequencies

GnomAD3 genomes AF: 0.754 AC: 114210 AN: 151514 Hom.: 43162 Cov.: 31

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.750

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.731

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.750

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.754 AC: 114310 AN: 151632 Hom.: 43201 Cov.: 31 AF XY: 0.750 AC XY: 55592 AN XY: 74080

African (AFR) AF: 0.796 AC: 32953 AN: 41386

American (AMR) AF: 0.808 AC: 12262 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 2592 AN: 3456

East Asian (EAS) AF: 0.625 AC: 3202 AN: 5122

South Asian (SAS) AF: 0.731 AC: 3517 AN: 4810

European-Finnish (FIN) AF: 0.666 AC: 7031 AN: 10554

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50396 AN: 67814

Other (OTH) AF: 0.747 AC: 1573 AN: 2106

Alfa AF: 0.747 Hom.: 21880

Bravo AF: 0.765

Asia WGS AF: 0.657 AC: 2289 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs339536; hg19: chr13-60551414;