rs863225243

Positions:

• chr5-141528456-G-A
• chr5-141528456-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005219.5(DIAPH1):​c.3145C>T​(p.Arg1049Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,858 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.25

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-141528456-G-A is Pathogenic according to our data. Variant chr5-141528456-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-141528456-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.3145C>T	p.Arg1049Ter	stop_gained	23/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.3145C>T	p.Arg1049Ter	stop_gained	23/28	5	NM_005219.5	ENSP00000373706	A2
DIAPH1	ENST00000518047.5	c.3118C>T	p.Arg1040Ter	stop_gained	22/27	5		ENSP00000428268	P4
DIAPH1	ENST00000647433.1	c.3145C>T	p.Arg1049Ter	stop_gained	23/29			ENSP00000494675	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000360 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2016

The R1049X pathogenic variant in the DIAPH1 gene has been reported in the homozygous state in association with syndromic microcephaly including seizures, developmental delay, vision loss, and facial dysmorphism (Yavarna et al., 2015; Al-Maawali et al., 2016). In addition, the R1049X variant was reported in an abstract by Kim et al. (2014) in the heterozygous state as co-segregating with a dominant form of hearing loss in a single family. The R1049X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R1049X as a pathogenic variant. -

Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 13, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.81	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
Vest4		0.86
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs863225243; hg19: chr5-140908023;