chr13-60042690-C-A

Variant names:

• chr13-60042690-C-A
• NM_001042517.2:c.626G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001042517.2(DIAPH3):​c.626G>T​(p.Ser209Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIAPH3 NM_001042517.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.28
• 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-AS1 (HGNC:39915): (DIAPH3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

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.626G>T	p.Ser209Ile	missense splice_region	Exon 5 of 28	NP_001035982.1	Q9NSV4-3
	DIAPH3	NM_001258366.2		c.593G>T	p.Ser198Ile	missense splice_region	Exon 4 of 27	NP_001245295.1	Q9NSV4-4
	DIAPH3	NM_001258367.2		c.488G>T	p.Ser163Ile	missense splice_region	Exon 3 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.626G>T	p.Ser209Ile	missense splice_region	Exon 5 of 28	ENSP00000383178.3	Q9NSV4-3
	DIAPH3	ENST00000377908.6	TSL:1	c.593G>T	p.Ser198Ile	missense splice_region	Exon 4 of 27	ENSP00000367141.2	Q9NSV4-4
	DIAPH3	ENST00000400320.5	TSL:1	c.488G>T	p.Ser163Ile	missense splice_region	Exon 3 of 26	ENSP00000383174.1	Q9NSV4-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant auditory neuropathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.50		Loss of disorder (P = 0.0383)
MVP		0.99
MPC		0.62
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.47
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.47		Position offset: 0

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

Other links and lift over

hg19: chr13-60616824;