rs876657776

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_Moderate PS3 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 benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000271650: A mouse model expressing the p.Arg1213X variant exhibited progressive hearing loss and loss of inner and outer hair cells. Homozygous mice exhibited an exacerbated hearing loss (Ueyama 2016). Additional studies performed in transfected cells indicate that this variant may result in constitutive activation of the DIAPH1 protein, a member of the formin protein family, which nucleate and elongate actin (Ueyama 2016)." and additional evidence is available in ClinVar.

• 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
• Publications: 16 publications found

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]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000271650: A mouse model expressing the p.Arg1213X variant exhibited progressive hearing loss and loss of inner and outer hair cells. Homozygous mice exhibited an exacerbated hearing loss (Ueyama 2016). Additional studies performed in transfected cells indicate that this variant may result in constitutive activation of the DIAPH1 protein, a member of the formin protein family, which nucleate and elongate actin (Ueyama 2016).; SCV001779356: Published functional studies demonstrate the p.(R1213X) variant causes increased activity as compared to wild-type (PMID: 26912466, 27707755).; SCV003439205: 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).
• 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 VariationId is 228577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. 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
	DIAPH1	NM_005219.5	MANE Select	c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 28	NP_005210.3
	DIAPH1	NM_001079812.3		c.3610C>T	p.Arg1204*	stop_gained	Exon 26 of 27	NP_001073280.1	O60610-3
	DIAPH1	NM_001314007.2		c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 28	ENSP00000373706.4	O60610-1
	DIAPH1	ENST00000518047.5	TSL:5	c.3610C>T	p.Arg1204*	stop_gained	Exon 26 of 27	ENSP00000428268.2	O60610-3
	DIAPH1	ENST00000647433.1		c.3637C>T	p.Arg1213*	stop_gained	Exon 27 of 29	ENSP00000494675.1	A0A2R8Y5N1

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Autosomal dominant nonsyndromic hearing loss 1 (2)
1	-	-	Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.1
Vest4		0.79
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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