5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGA

Position:

• chr5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGA

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6 BS2_Supporting

The NM_005219.5(DIAPH1):​c.1845_1853del​(p.Pro618_Pro620del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000708 in 1,511,874 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 0.000096 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000069 (1 hom.)
• Consequence: DIAPH1 NM_005219.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 -2 ACMG points.

• BP6: Variant 5-141573996-TGGAGGAGGA-T is Benign according to our data. Variant chr5-141573996-TGGAGGAGGA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 593399.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 12 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.1845_1853del	p.Pro618_Pro620del	inframe_deletion	16/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1845_1853del	p.Pro618_Pro620del	inframe_deletion	16/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.1818_1826del	p.Pro609_Pro611del	inframe_deletion	15/27	5		P4
DIAPH1	ENST00000647433.1	c.1845_1853del	p.Pro618_Pro620del	inframe_deletion	16/29			A2
DIAPH1	ENST00000647330.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0000956 AC: 12 AN: 125476 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000230

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000856

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000685 AC: 95 AN: 1386328 Hom.: 1 AF XY: 0.0000775 AC XY: 53 AN XY: 683650

Gnomad4 AFR exome AF: 0.000191

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000809

Gnomad4 EAS exome AF: 0.000311

Gnomad4 SAS exome AF: 0.0000771

Gnomad4 FIN exome AF: 0.0000210

Gnomad4 NFE exome AF: 0.0000560

Gnomad4 OTH exome AF: 0.000122

GnomAD4 genome AF: 0.0000956 AC: 12 AN: 125546 Hom.: 0 Cov.: 28 AF XY: 0.000149 AC XY: 9 AN XY: 60228

Gnomad4 AFR AF: 0.000151

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000230

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000129

Gnomad4 NFE AF: 0.0000856

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Mar 27, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 593399). This variant has been observed in individual(s) with epilepsy (Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.1845_1853del, results in the deletion of 3 amino acid(s) of the DIAPH1 protein (p.Pro618_Pro620del), but otherwise preserves the integrity of the reading frame. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2017

- -

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;