rs876657776

Positions:

• chr5-141524167-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_005219.5(DIAPH1):​c.3637C>T​(p.Arg1213Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,874 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.14

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0477 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-141524167-G-A is Pathogenic according to our data. Variant chr5-141524167-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 228577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-141524167-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3637C>T	p.Arg1213Ter	stop_gained	27/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3637C>T	p.Arg1213Ter	stop_gained	27/28	5	NM_005219.5	ENSP00000373706	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461874 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2024	Identified in multiple unrelated individuals with autosomal dominant sensorineural hearing loss in published literature; thrombocytopenia was also reported in several families (PMID: 28983057, 27911912, 26912466, 27808407, 27707755); Published functional studies demonstrate the p.(R1213X) variant causes increased activity as compared to wild-type (PMID: 26912466, 27707755); Nonsense variant predicted to result in protein truncation as the last 60 amino acids are lost; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27808407, 37543941, 34232383, 27707755, 29985732, 27911912, 28815995, 31152317, 31473629, 32594080, 34223798, 28983057, 26912466) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2018	- -

Autosomal dominant nonsyndromic hearing loss 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 25, 2019	- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 04, 2018

The p.Arg1213X variant in DIAPH1 has been reported in six probands with either h earing loss or hearing loss with thrombocytopenia and segregated in 10 affected family members (Iwasa 2016, Stritt 2016, Ueyama 2016, Neuhaus 2017). This varian t was absent from large population studies. A mouse model expressing the p.Arg12 13X variant exhibited progressive hearing loss and loss of inner and outer hair cells. Homozygous mice exhibited an exacerbated hearing loss (Ueyama 2016). Addi tional studies performed in transfected cells indicate that this variant may res ult in constitutive activation of the DIAPH1 protein, a member of the formin pro tein family, which nucleate and elongate actin (Ueyama 2016). Furthermore, cultu red megakaryocytes from patients harboring p.Arg1213X showed reduced proplatelet formation, cell clustering and abnormal cortical filamentous actin, and platele ts had increased actin and stable microtubules. RT-PCR performed on samples from 2 probands showed presence of both wild-type and Arg1213X mRNA, suggesting that the DIAPH1 is prematurely truncated. Collectively, the functional evidence sugg ests either a gain-of-function or dominant negative effect. In summary, this var iant meets criteria to be classified as pathogenic for autosomal dominant hearin g loss with thrombocytopenia. ACMG/AMP criteria applied: PS3, PP1_Strong, PM2, P S4_Moderate. -

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects DIAPH1 function leading to constitutive activation for gain-of-function (PMID: 26912466, 27707755, 32678080). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 228577). This variant is also known as c.3610C>T (R1204X). This premature translational stop signal has been observed in individual(s) with autosomal dominant hearing loss with or without macrothrombocytopenia (PMID: 26912466, 27707755, 27808407, 27911912, 28815995, 28983057). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1213*) in the DIAPH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the DIAPH1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
Vest4		0.79
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs876657776; hg19: chr5-140903734; COSMIC: COSV53879507; COSMIC: COSV53879507;