13-59666690-T-G

Variant names:

• chr13-59666690-T-G
• NM_001042517.2:c.3476A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001042517.2(DIAPH3):​c.3476A>C​(p.Asn1159Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N1159N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIAPH3 NM_001042517.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108649135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH3	NM_001042517.2	c.3476A>C	p.Asn1159Thr	missense_variant	Exon 28 of 28	ENST00000400324.9	NP_001035982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH3	ENST00000400324.9	c.3476A>C	p.Asn1159Thr	missense_variant	Exon 28 of 28	1	NM_001042517.2	ENSP00000383178.3
DIAPH3	ENST00000400319.5	c.3266A>C	p.Asn1089Thr	missense_variant	Exon 26 of 26	1		ENSP00000383173.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3476A>C (p.N1159T) alteration is located in exon 28 (coding exon 28) of the DIAPH3 gene. This alteration results from a A to C substitution at nucleotide position 3476, causing the asparagine (N) at amino acid position 1159 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;.;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.55	N;.;.;.
PhyloP100		2.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.085	T;T;T;T
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.0	B;.;.;.
Vest4		0.069
MutPred		0.12		Gain of phosphorylation at N1159 (P = 0.0495);.;.;.;
MVP		0.61
MPC		0.16
ClinPred		0.26	T
GERP RS		1.3
Varity_R		0.080
gMVP		0.23
Mutation Taster		=96/4	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

hg19: chr13-60240824;