5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGA

Variant names:

• chr5-141573996-TGGAGGAGGAGGA-T
• rs3075570
• NM_005219.5:c.1842_1853delTCCTCCTCCTCC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_005219.5(DIAPH1):​c.1842_1853delTCCTCCTCCTCC​(p.Pro615_Pro618del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00047 in 1,511,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• 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 -5 ACMG points.

• BP6: Variant 5-141573996-TGGAGGAGGAGGA-T is Benign according to our data. Variant chr5-141573996-TGGAGGAGGAGGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.1842_1853delTCCTCCTCCTCC	p.Pro615_Pro618del	disruptive_inframe_deletion	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.1842_1853delTCCTCCTCCTCC	p.Pro615_Pro618del	disruptive_inframe_deletion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.1815_1826delTCCTCCTCCTCC	p.Pro606_Pro609del	disruptive_inframe_deletion	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.1842_1853delTCCTCCTCCTCC	p.Pro615_Pro618del	disruptive_inframe_deletion	Exon 16 of 29			ENSP00000494675.1
DIAPH1	ENST00000647330.1	n.*1069_*1080delTCCTCCTCCTCC		downstream_gene_variant				ENSP00000494308.1

Frequencies

GnomAD3 genomes AF: 0.000550 AC: 69 AN: 125476 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000805

Gnomad ASJ AF: 0.000325

Gnomad EAS AF: 0.000230

Gnomad SAS AF: 0.000265

Gnomad FIN AF: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000821

Gnomad OTH AF: 0.000596

GnomAD4 exome AF: 0.000463 AC: 642 AN: 1386328 Hom.: 0 AF XY: 0.000489 AC XY: 334 AN XY: 683644

Gnomad4 AFR exome AF: 0.000223

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.0000809

Gnomad4 EAS exome AF: 0.000905

Gnomad4 SAS exome AF: 0.000257

Gnomad4 FIN exome AF: 0.000147

Gnomad4 NFE exome AF: 0.000507

Gnomad4 OTH exome AF: 0.000400

GnomAD4 genome AF: 0.000550 AC: 69 AN: 125476 Hom.: 0 Cov.: 28 AF XY: 0.000615 AC XY: 37 AN XY: 60150

Gnomad4 AFR AF: 0.000455

Gnomad4 AMR AF: 0.0000805

Gnomad4 ASJ AF: 0.000325

Gnomad4 EAS AF: 0.000230

Gnomad4 SAS AF: 0.000265

Gnomad4 FIN AF: 0.000129

Gnomad4 NFE AF: 0.000821

Gnomad4 OTH AF: 0.000596

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

May 12, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Benign:2

Apr 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DIAPH1-related disorder Uncertain:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DIAPH1 c.1842_1853del12 variant is predicted to result in an in-frame deletion (p.Pro617_Pro620del). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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;