rs189809247

Positions:

• chr5-141574081-C-A
• chr5-141574081-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.15

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 -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=5, 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	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	c.1769G>T	p.Gly590Val	missense_variant	16/28	5	NM_005219.5	A2
DIAPH1	ENST00000518047.5	c.1742G>T	p.Gly581Val	missense_variant	15/27	5		P4
DIAPH1	ENST00000647433.1	c.1769G>T	p.Gly590Val	missense_variant	16/29			A2
DIAPH1	ENST00000647330.1	c.*996G>T		3_prime_UTR_variant, NMD_transcript_variant	15/15

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 226 AN: 151414 Hom.: 0 Cov.: 31

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.: 1 AF XY: 0.00119 AC XY: 160 AN XY: 133990

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.: 3 Cov.: 36 AF XY: 0.00154 AC XY: 1120 AN XY: 726458

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.: 0 Cov.: 31 AF XY: 0.00143 AC XY: 106 AN XY: 74022

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.: 1

Bravo AF: 0.00106

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00190 AC: 16

ExAC AF: 0.00118 AC: 143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

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

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, criteria provided, single submitter

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

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
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	N
LIST_S2	Benign	0.76	T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0074	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs189809247; hg19: chr5-140953648;