chr5-141524167-G-A

Variant names:

• chr5-141524167-G-A
• rs876657776
• NM_005219.5:c.3637C>T

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.Arg1213*) 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 rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.3610C>T	p.Arg1204*	stop_gained	Exon 26 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 29			ENSP00000494675.1
DIAPH1	ENST00000468119.3	c.43C>T	p.Arg15*	stop_gained	Exon 2 of 3	4		ENSP00000493546.1

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

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jun 19, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 1 Pathogenic:2

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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Rare genetic deafness Pathogenic:1

Nov 04, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (gnomAD no frequency). 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 also known as c.3610C>T (R1204X). ClinVar contains an entry for this variant (Variation ID: 228577). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. 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). For these reasons, this variant has been classified as Pathogenic. -

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
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;