NM_005219.5:c.1845_1853dupTCCTCCTCC

Variant names:

• chr5-141573996-T-TGGAGGAGGA
• rs3075570
• NM_005219.5:c.1845_1853dupTCCTCCTCC

Variant summary

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

The NM_005219.5(DIAPH1):​c.1845_1853dupTCCTCCTCC​(p.Pro616_Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 125,544 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 0.0012 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00075 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B: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 Benign. Variant got -9 ACMG points.

• BP6: Variant 5-141573996-T-TGGAGGAGGA is Benign according to our data. Variant chr5-141573996-T-TGGAGGAGGA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542361.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0012 (151/125544) while in subpopulation AMR AF= 0.0037 (46/12438). AF 95% confidence interval is 0.00285. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.1845_1853dupTCCTCCTCC	p.Pro616_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.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.1818_1826dupTCCTCCTCC	p.Pro607_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.1845_1853dupTCCTCCTCC	p.Pro616_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29			ENSP00000494675.1
DIAPH1	ENST00000647330.1	n.*1072_*1080dupTCCTCCTCC		downstream_gene_variant				ENSP00000494308.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 150 AN: 125474 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00370

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00161

Gnomad SAS AF: 0.00212

Gnomad FIN AF: 0.00232

Gnomad MID AF: 0.00442

Gnomad NFE AF: 0.000924

Gnomad OTH AF: 0.00119

GnomAD3 exomes AF: 0.00160 AC: 134 AN: 83800 Hom.: 0 AF XY: 0.00154 AC XY: 67 AN XY: 43632

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00478

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.000884

Gnomad OTH exome AF: 0.000436

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000752 AC: 1042 AN: 1386248 Hom.: 1 Cov.: 35 AF XY: 0.000772 AC XY: 528 AN XY: 683600

Gnomad4 AFR exome AF: 0.000669

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000905

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.000638

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00120 AC: 151 AN: 125544 Hom.: 0 Cov.: 28 AF XY: 0.00130 AC XY: 78 AN XY: 60228

Gnomad4 AFR AF: 0.000454

Gnomad4 AMR AF: 0.00370

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00161

Gnomad4 SAS AF: 0.00212

Gnomad4 FIN AF: 0.00232

Gnomad4 NFE AF: 0.000924

Gnomad4 OTH AF: 0.00118

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Nov 12, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1845_1853dupTCCTCCTCC, results in the insertion of 3 amino acids to the DIAPH1 protein (p.Pro618_Pro620dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DIAPH1-related disease. ClinVar contains an entry for this variant (Variation ID: 542361). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acids 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. -

Inborn genetic diseases Benign:1

Oct 26, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DIAPH1-related disorder Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;