rs730882242

Variant names:

• chr5-141573518-G-A
• rs730882242
• NM_005219.5:c.2332C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005219.5(DIAPH1):​c.2332C>T​(p.Gln778*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,460,860 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 4.54
• Publications: 9 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: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-141573518-G-A is Pathogenic according to our data. Variant chr5-141573518-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.2332C>T	p.Gln778*	stop_gained	Exon 16 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8	c.2332C>T	p.Gln778*	stop_gained	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.2305C>T	p.Gln769*	stop_gained	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.2332C>T	p.Gln778*	stop_gained	Exon 16 of 29			ENSP00000494675.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460860 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 726734

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.000533 AC: 3 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111464

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Pathogenic:2

May 08, 2023

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal dominant nonsyndromic hearing loss 1 Pathogenic:1

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Epilepsy;C0557874:Global developmental delay;C2315100:Failure to thrive;C4551563:Microcephaly Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		4.5
Vest4		0.85
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs730882242; hg19: chr5-140953085;