5-141527689-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005219.5(DIAPH1):c.3157G>A(p.Glu1053Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000324 in 616,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.25

Publications

0 publications found

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 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

DIAPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.3157G>A	p.Glu1053Lys	missense_variant	Exon 24 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DIAPH1	ENST00000389054.8 link	c.3157G>A	p.Glu1053Lys	missense_variant	Exon 24 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5 link	c.3130G>A	p.Glu1044Lys	missense_variant	Exon 23 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1 link	c.3157G>A	p.Glu1053Lys	missense_variant	Exon 24 of 29			ENSP00000494675.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111264

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000324

AC:

AN:

616520

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

319506

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13872

American (AMR)

AF:

0.00

AC:

AN:

23920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13174

East Asian (EAS)

AF:

0.00

AC:

AN:

20516

South Asian (SAS)

AF:

0.00

AC:

AN:

47574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2028

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

432744

Other (OTH)

AF:

0.0000778

AC:

AN:

25716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

111264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

51508

African (AFR)

AF:

0.00

AC:

AN:

28394

American (AMR)

AF:

0.00

AC:

AN:

9216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3042

East Asian (EAS)

AF:

0.00

AC:

AN:

3714

South Asian (SAS)

AF:

0.00

AC:

AN:

3388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3960

Middle Eastern (MID)

AF:

0.00

AC:

AN:

186

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

57190

Other (OTH)

AF:

0.00

AC:

AN:

1406

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Uncertain:2

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 575625). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1053 of the DIAPH1 protein (p.Glu1053Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;T;.;T;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;D;D;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.54

D;D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;.;.;.;.

PhyloP100

3.3

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.3

.;.;.;N;N;.

REVEL

Benign

0.28

Sift

Uncertain

0.023

.;.;.;D;D;.

Sift4G

Benign

0.12

T;.;T;T;T;T

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.55

MutPred

0.47

Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);.;.;Gain of MoRF binding (P = 0.0025);.;

MVP

0.71

MPC

1.4

ClinPred

0.97

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.47

gMVP

0.41

Mutation Taster

=41/59

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over