5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGA

Position:

• chr5-141573996-TGGAGGAGGAGGAGGAGGAGGA-TGGAGGAGGAGGAGGAGGAGGAGGA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005219.5(DIAPH1):​c.1853_1854insTCC​(p.Pro619dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,510,582 control chromosomes in the GnomAD database, including 343 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P618P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.046 (162 hom., cov: 28)
  • Exomes 𝑓: 0.030 (181 hom.)
• Consequence: DIAPH1 NM_005219.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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 -16 ACMG points.

• BP6: Variant 5-141573996-T-TGGA is Benign according to our data. Variant chr5-141573996-T-TGGA is described in ClinVar as [Likely_benign]. Clinvar id is 226564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.088 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5	c.1853_1854insTCC	p.Pro619dup	inframe_insertion	16/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8	c.1853_1854insTCC	p.Pro619dup	inframe_insertion	16/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.1826_1827insTCC	p.Pro610dup	inframe_insertion	15/27	5		P4
DIAPH1	ENST00000647433.1	c.1853_1854insTCC	p.Pro619dup	inframe_insertion	16/29			A2
DIAPH1	ENST00000647330.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 5727 AN: 125396 Hom.: 162 Cov.: 28

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0526

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.0207

Gnomad FIN AF: 0.00618

Gnomad MID AF: 0.0310

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0369

GnomAD3 exomes AF: 0.0450 AC: 3773 AN: 83800 Hom.: 11 AF XY: 0.0457 AC XY: 1996 AN XY: 43632

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0433

Gnomad ASJ exome AF: 0.0676

Gnomad EAS exome AF: 0.0539

Gnomad SAS exome AF: 0.0450

Gnomad FIN exome AF: 0.00691

Gnomad NFE exome AF: 0.0407

Gnomad OTH exome AF: 0.0536

GnomAD4 exome AF: 0.0299 AC: 41374 AN: 1385114 Hom.: 181 Cov.: 35 AF XY: 0.0296 AC XY: 20243 AN XY: 683052

Gnomad4 AFR exome AF: 0.0799

Gnomad4 AMR exome AF: 0.0248

Gnomad4 ASJ exome AF: 0.0467

Gnomad4 EAS exome AF: 0.0279

Gnomad4 SAS exome AF: 0.0243

Gnomad4 FIN exome AF: 0.00671

Gnomad4 NFE exome AF: 0.0294

Gnomad4 OTH exome AF: 0.0349

GnomAD4 genome AF: 0.0457 AC: 5733 AN: 125468 Hom.: 162 Cov.: 28 AF XY: 0.0447 AC XY: 2693 AN XY: 60188

Gnomad4 AFR AF: 0.0907

Gnomad4 AMR AF: 0.0300

Gnomad4 ASJ AF: 0.0526

Gnomad4 EAS AF: 0.0291

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.00618

Gnomad4 NFE AF: 0.0311

Gnomad4 OTH AF: 0.0384

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 31, 2014	c.1821TCC[12] in exon 16 of DIAPH1: This allele is a part of a poly TCC stretch and is not expected to have clinical significance because it has been identified in 3.1% (238/7732) of European American chromosomes and 6.7% (239/3592) of Afri can American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS/; dbSNP rs35249032). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2015	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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

Feb 01, 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;