chr5-141573996-T-TGGAGGAGGAGGAGGA

Variant names:

• chr5-141573996-T-TGGAGGAGGAGGAGGA
• rs3075570
• NM_005219.5:c.1839_1853dupTCCTCCTCCTCCTCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BP6_Very_Strong

The NM_005219.5(DIAPH1):​c.1839_1853dupTCCTCCTCCTCCTCC​(p.Pro614_Pro618dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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 0.0024 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0029 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIAPH1 NM_005219.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.13
• Publications: 2 publications found

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]

DIAPH1 Gene-Disease associations (from GenCC):

• DIAPH1-related sensorineural hearing loss-thrombocytopenia syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• autosomal dominant nonsyndromic hearing loss 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_005219.5
• BP6: Variant 5-141573996-T-TGGAGGAGGAGGAGGA is Benign according to our data. Variant chr5-141573996-T-TGGAGGAGGAGGAGGA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 568618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5	c.1839_1853dupTCCTCCTCCTCCTCC	p.Pro614_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.1839_1853dupTCCTCCTCCTCCTCC	p.Pro614_Pro618dup	disruptive_inframe_insertion	Exon 16 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5	c.1812_1826dupTCCTCCTCCTCCTCC	p.Pro605_Pro609dup	disruptive_inframe_insertion	Exon 15 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1	c.1839_1853dupTCCTCCTCCTCCTCC	p.Pro614_Pro618dup	disruptive_inframe_insertion	Exon 16 of 29			ENSP00000494675.1
DIAPH1	ENST00000647330.1	n.*1066_*1080dupTCCTCCTCCTCCTCC		downstream_gene_variant				ENSP00000494308.1

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 300 AN: 125452 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000230

Gnomad SAS AF: 0.000265

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00358

GnomAD2 exomes AF: 0.00376 AC: 315 AN: 83800 AF XY: 0.00337

Gnomad AFR exome AF: 0.00165

Gnomad AMR exome AF: 0.0112

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.000184

Gnomad FIN exome AF: 0.000119

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00915

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00286 AC: 3969 AN: 1385352 Hom.: 11 Cov.: 35 AF XY: 0.00286 AC XY: 1954 AN XY: 683140

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000606 AC: 19 AN: 31376

American (AMR) AF: 0.00625 AC: 220 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.000162 AC: 4 AN: 24730

East Asian (EAS) AF: 0.000113 AC: 4 AN: 35360

South Asian (SAS) AF: 0.0000385 AC: 3 AN: 77858

European-Finnish (FIN) AF: 0.000189 AC: 9 AN: 47514

Middle Eastern (MID) AF: 0.00158 AC: 7 AN: 4442

European-Non Finnish (NFE) AF: 0.00330 AC: 3539 AN: 1071470

Other (OTH) AF: 0.00286 AC: 164 AN: 57416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00239 AC: 300 AN: 125522 Hom.: 1 Cov.: 28 AF XY: 0.00223 AC XY: 134 AN XY: 60214

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000454 AC: 15 AN: 33032

American (AMR) AF: 0.00563 AC: 70 AN: 12428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3078

East Asian (EAS) AF: 0.000230 AC: 1 AN: 4344

South Asian (SAS) AF: 0.000266 AC: 1 AN: 3766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 208

European-Non Finnish (NFE) AF: 0.00354 AC: 207 AN: 58408

Other (OTH) AF: 0.00355 AC: 6 AN: 1690

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00102 Hom.: 2

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 15, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DIAPH1: BS2 -

Inborn genetic diseases Benign:1

Jun 03, 2022

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. -

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=77/23	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3075570; hg19: chr5-140953563;