5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGA

Position:

• chr5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005219.5(DIAPH1):​c.1848_1853del​(p.Pro619_Pro620del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000591 in 1,511,370 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00057 (1 hom.)
• Consequence: DIAPH1 NM_005219.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• 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 Benign. Variant got -9 ACMG points.

• BP6: Variant 5-141573996-TGGAGGA-T is Benign according to our data. Variant chr5-141573996-TGGAGGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351294.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}. Variant chr5-141573996-TGGAGGA-T is described in Lovd as [Likely_benign]. Variant chr5-141573996-TGGAGGA-T is described in Lovd as [Likely_benign]. Variant chr5-141573996-TGGAGGA-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000876 (110/125546) while in subpopulation EAS AF= 0.00967 (42/4344). AF 95% confidence interval is 0.00735. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.1848_1853del	p.Pro619_Pro620del	inframe_deletion	16/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1848_1853del	p.Pro619_Pro620del	inframe_deletion	16/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.1821_1826del	p.Pro610_Pro611del	inframe_deletion	15/27	5		P4
DIAPH1	ENST00000647433.1	c.1848_1853del	p.Pro619_Pro620del	inframe_deletion	16/29			A2
DIAPH1	ENST00000647330.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000885 AC: 111 AN: 125476 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000805

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00965

Gnomad SAS AF: 0.00371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00442

Gnomad NFE AF: 0.000240

Gnomad OTH AF: 0.00179

GnomAD3 exomes AF: 0.00248 AC: 208 AN: 83800 Hom.: 0 AF XY: 0.00241 AC XY: 105 AN XY: 43632

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000720

Gnomad ASJ exome AF: 0.000405

Gnomad EAS exome AF: 0.0177

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.000596

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.000565 AC: 783 AN: 1385824 Hom.: 1 AF XY: 0.000623 AC XY: 426 AN XY: 683432

Gnomad4 AFR exome AF: 0.000669

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.000284

Gnomad4 EAS exome AF: 0.00701

Gnomad4 SAS exome AF: 0.00263

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.000876 AC: 110 AN: 125546 Hom.: 0 Cov.: 28 AF XY: 0.000946 AC XY: 57 AN XY: 60230

Gnomad4 AFR AF: 0.000817

Gnomad4 AMR AF: 0.000804

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00967

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000240

Gnomad4 OTH AF: 0.00177

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	DIAPH1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2018	- -

Nonsyndromic Hearing Loss, Mixed Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Pro619_Pro620del in exon 16 of DIAPH1: This variant is not expected to have cl inical significance because it has been identified in 2.77% (14/506) of East Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs760344729). -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

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;