rs2074913

Positions:

chr5-141618784-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005219.5(DIAPH1):c.117+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,532,352 control chromosomes in the GnomAD database, including 4,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 359 hom., cov: 32)

Exomes 𝑓: 0.069 ( 3738 hom. )

Consequence

DIAPH1
NM_005219.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.88

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 5-141618784-G-A is Benign according to our data. Variant chr5-141618784-G-A is described in ClinVar as [Benign]. Clinvar id is 45212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-141618784-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
DIAPH1	NM_005219.5 linkuse as main transcript	c.117+14C>T	intron_variant	ENST00000389054.8
DIAPH1	NM_001079812.3 linkuse as main transcript	c.117+14C>T	intron_variant
DIAPH1	NM_001314007.2 linkuse as main transcript	c.117+14C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8 linkuse as main transcript	c.117+14C>T		intron_variant		5	NM_005219.5	A2	O60610-1
	ENST00000422040.2 linkuse as main transcript	n.76+295G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0576

AC:

8764

AN:

152134

Hom.:

361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0366

Gnomad ASJ

AF:

0.0907

Gnomad EAS

AF:

0.0432

Gnomad SAS

AF:

0.0500

Gnomad FIN

AF:

0.124

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0791

Gnomad OTH

AF:

0.0755

GnomAD3 exomes

AF:

0.0627

AC:

10183

AN:

162482

Hom.:

412

AF XY:

0.0624

AC XY:

5486

AN XY:

87938

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.0291

Gnomad ASJ exome

AF:

0.0834

Gnomad EAS exome

AF:

0.0407

Gnomad SAS exome

AF:

0.0512

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.0721

Gnomad OTH exome

AF:

0.0647

GnomAD4 exome

AF:

0.0691

AC:

95427

AN:

1380102

Hom.:

3738

Cov.:

AF XY:

0.0691

AC XY:

47246

AN XY:

683928

show subpopulations

Gnomad4 AFR exome

AF:

0.0112

Gnomad4 AMR exome

AF:

0.0317

Gnomad4 ASJ exome

AF:

0.0824

Gnomad4 EAS exome

AF:

0.0271

Gnomad4 SAS exome

AF:

0.0515

Gnomad4 FIN exome

AF:

0.121

Gnomad4 NFE exome

AF:

0.0722

Gnomad4 OTH exome

AF:

0.0677

GnomAD4 genome

AF:

0.0576

AC:

8767

AN:

152250

Hom.:

359

Cov.:

AF XY:

0.0588

AC XY:

4377

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0126

Gnomad4 AMR

AF:

0.0366

Gnomad4 ASJ

AF:

0.0907

Gnomad4 EAS

AF:

0.0436

Gnomad4 SAS

AF:

0.0499

Gnomad4 FIN

AF:

0.124

Gnomad4 NFE

AF:

0.0791

Gnomad4 OTH

AF:

0.0776

Alfa

AF:

0.0710

Hom.:

125

Bravo

AF:

0.0477

Asia WGS

AF:

0.0860

AC:

297

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	117+14C>T in Intron 01 of DIAPH1: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 7.3% (459/6300) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs2074913). -

Autosomal dominant nonsyndromic hearing loss 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2018

- -

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

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over