5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGAGGA

Variant names:

• chr5-141573996-T-TGGAGGAGGAGGAGGAGGAGGA
• rs3075570
• NM_005219.5:c.1833_1853dupTCCTCCTCCTCCTCCTCCTCC

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_005219.5(DIAPH1):​c.1833_1853dupTCCTCCTCCTCCTCCTCCTCC​(p.Pro612_Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.13

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.1833_1853dupTCCTCCTCCTCCTCCTCCTCC	p.Pro612_Pro618dup	disruptive_inframe_insertion	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.1833_1853dupTCCTCCTCCTCCTCCTCCTCC	p.Pro612_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.1806_1826dupTCCTCCTCCTCCTCCTCCTCC	p.Pro603_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.1833_1853dupTCCTCCTCCTCCTCCTCCTCC	p.Pro612_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29			ENSP00000494675.1
DIAPH1	ENST00000647330.1	n.*1060_*1080dupTCCTCCTCCTCCTCCTCCTCC		downstream_gene_variant				ENSP00000494308.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 31 AN: 125476 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000260 AC: 36 AN: 1386308 Hom.: 0 Cov.: 35 AF XY: 0.0000176 AC XY: 12 AN XY: 683638

Gnomad4 AFR exome AF: 0.000797

Gnomad4 AMR exome AF: 0.0000283

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000257

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000560

Gnomad4 OTH exome AF: 0.0000348

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000247 AC: 31 AN: 125546 Hom.: 0 Cov.: 28 AF XY: 0.000249 AC XY: 15 AN XY: 60230

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1833_1853dupTCCTCCTCCTCCTCCTCCTCC (p.P614_P620dup) alteration is located in exon 16 (coding exon 16) of the DIAPH1 gene. The alteration consists of an in-frame duplication of 21 nucleotides from position 1833 to 1853, resulting in the duplication of 7 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Jan 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant, c.1833_1853dup, results in the insertion of 7 amino acid(s) of the DIAPH1 protein (p.Pro614_Pro620dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 951411). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. -

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;