chr13-60016086-A-G

Variant names:

• chr13-60016086-A-G
• rs201688909
• NM_001042517.2:c.686T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_001042517.2(DIAPH3):​c.686T>C​(p.Leu229Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,613,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L229V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: DIAPH3 NM_001042517.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.94
• Publications: 2 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 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• BS2: High AC in GnomAd4 at 18 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.686T>C	p.Leu229Pro	missense	Exon 6 of 28	NP_001035982.1	Q9NSV4-3
	DIAPH3	NM_001258366.2		c.653T>C	p.Leu218Pro	missense	Exon 5 of 27	NP_001245295.1	Q9NSV4-4
	DIAPH3	NM_001258367.2		c.548T>C	p.Leu183Pro	missense	Exon 4 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.686T>C	p.Leu229Pro	missense	Exon 6 of 28	ENSP00000383178.3	Q9NSV4-3
	DIAPH3	ENST00000377908.6	TSL:1	c.653T>C	p.Leu218Pro	missense	Exon 5 of 27	ENSP00000367141.2	Q9NSV4-4
	DIAPH3	ENST00000400320.5	TSL:1	c.548T>C	p.Leu183Pro	missense	Exon 4 of 26	ENSP00000383174.1	Q9NSV4-5

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000725 AC: 18 AN: 248352 AF XY: 0.0000668

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000130 AC: 190 AN: 1461310 Hom.: 0 Cov.: 32 AF XY: 0.000114 AC XY: 83 AN XY: 726962

African (AFR) AF: 0.0000896 AC: 3 AN: 33464

American (AMR) AF: 0.0000671 AC: 3 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000162 AC: 180 AN: 1111722

Other (OTH) AF: 0.0000663 AC: 4 AN: 60360

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74358

African (AFR) AF: 0.0000483 AC: 2 AN: 41434

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68052

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.000277 AC: 1

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.0000745 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.99
MPC		0.75
ClinPred		0.88	D
GERP RS		6.2
Varity_R		0.95
gMVP		0.83
Mutation Taster		=28/72	disease causing

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: rs201688909; hg19: chr13-60590220;