5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGA

Position:

• chr5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005219.5(DIAPH1):​c.1839_1853del​(p.Pro616_Pro620del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000284 in 1,511,878 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000024 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000029 (1 hom.)
• Consequence: DIAPH1 NM_005219.5 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.53

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.1839_1853del	p.Pro616_Pro620del	inframe_deletion	16/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1839_1853del	p.Pro616_Pro620del	inframe_deletion	16/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.1812_1826del	p.Pro607_Pro611del	inframe_deletion	15/27	5		P4
DIAPH1	ENST00000647433.1	c.1839_1853del	p.Pro616_Pro620del	inframe_deletion	16/29			A2
DIAPH1	ENST00000647330.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000239 AC: 3 AN: 125476 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000529

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000289 AC: 40 AN: 1386332 Hom.: 1 AF XY: 0.0000366 AC XY: 25 AN XY: 683648

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000566

Gnomad4 SAS exome AF: 0.000283

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000121

Gnomad4 OTH exome AF: 0.0000522

GnomAD4 genome AF: 0.0000239 AC: 3 AN: 125546 Hom.: 0 Cov.: 28 AF XY: 0.0000332 AC XY: 2 AN XY: 60228

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000531

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000171

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 01, 2020

Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 5 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

ClinVar contains an entry for this variant (Variation ID: 1022074). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1839_1853del, results in the deletion of 5 amino acid(s) of the DIAPH1 protein (p.Pro616_Pro620del), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3075570; hg19: chr5-140953563;