13-60016126-G-T

Variant names:

• chr13-60016126-G-T
• rs770042088
• NM_001042517.2:c.646C>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001042517.2(DIAPH3):​c.646C>A​(p.His216Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DIAPH3 NM_001042517.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

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-AS1 (HGNC:39915): (DIAPH3 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3504511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH3	NM_001042517.2	c.646C>A	p.His216Asn	missense_variant	Exon 6 of 28	ENST00000400324.9	NP_001035982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH3	ENST00000400324.9	c.646C>A	p.His216Asn	missense_variant	Exon 6 of 28	1	NM_001042517.2	ENSP00000383178.3
DIAPH3	ENST00000400319.5	c.436C>A	p.His146Asn	missense_variant	Exon 4 of 26	1		ENSP00000383173.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248250 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461468 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 216 of the DIAPH3 protein (p.His216Asn). This variant is present in population databases (rs770042088, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DIAPH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 3011877). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.42	T;.;.;.;.
Eigen	Benign	-0.019
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Uncertain	-0.0056	T
MutationAssessor	Benign	0.90	L;.;.;.;L
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D
REVEL	Benign	0.28
Sift	Benign	0.40	T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.17	B;.;.;.;.
Vest4		0.31
MutPred		0.60		Gain of helix (P = 0.2059);.;.;.;Gain of helix (P = 0.2059);
MVP		0.88
MPC		0.20
ClinPred		0.25	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs770042088; hg19: chr13-60590260;