rs189809247

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005219.5(DIAPH1):c.1769G>T(p.Gly590Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,612,138 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G590D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007395059).

BP6

Variant 5-141574081-C-A is Benign according to our data. Variant chr5-141574081-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227300.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00149 (226/151532) while in subpopulation NFE AF= 0.00268 (182/67876). AF 95% confidence interval is 0.00236. There are 0 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 226 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIAPH1	NM_005219.5 linkuse as main transcript	c.1769G>T	p.Gly590Val	missense_variant	16/28	ENST00000389054.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIAPH1	ENST00000389054.8 linkuse as main transcript	c.1769G>T	p.Gly590Val	missense_variant	16/28	5	NM_005219.5	A2	O60610-1
DIAPH1	ENST00000518047.5 linkuse as main transcript	c.1742G>T	p.Gly581Val	missense_variant	15/27	5		P4	O60610-3
DIAPH1	ENST00000647433.1 linkuse as main transcript	c.1769G>T	p.Gly590Val	missense_variant	16/29			A2
DIAPH1	ENST00000647330.1 linkuse as main transcript	c.*996G>T		3_prime_UTR_variant, NMD_transcript_variant	15/15

Frequencies

GnomAD3 genomes

AF:

0.00149

AC:

226

AN:

151414

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00210

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00268

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.00123

AC:

304

AN:

247096

Hom.:

AF XY:

0.00119

AC XY:

160

AN XY:

133990

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000205

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00275

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00148

AC:

2164

AN:

1460606

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

1120

AN XY:

726458

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00287

Gnomad4 NFE exome

AF:

0.00171

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00149

AC:

226

AN:

151532

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

106

AN XY:

74022

show subpopulations

Gnomad4 AFR

AF:

0.000388

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00210

Gnomad4 NFE

AF:

0.00268

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.00106

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00190

AC:

ExAC

AF:

0.00118

AC:

143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2020	This variant is associated with the following publications: (PMID: 23804846) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DIAPH1: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 14, 2017

p.Gly590Val in exon 16 of DIAPH1: This variant is not expected to have clinical significance because it has been identified in 0.3% (69/25716) of Finnish and 0. 2% (283/125346) of European chromosomes, including 1 homozygous individual, by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs189809247). -

Autosomal dominant nonsyndromic hearing loss 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

DIAPH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2022

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). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;T;.;T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.76

T;T;T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.0074

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.99

N;.;N;N;N;N

REVEL

Benign

0.054

Sift

Uncertain

0.028

D;.;D;D;D;D

Sift4G

Benign

0.071

T;.;T;T;T;T

Polyphen

0.047

B;.;.;.;.;.

Vest4

0.23

MVP

0.54

MPC

0.14

ClinPred

0.041

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.051

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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