5-141573751-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005219.5(DIAPH1):c.2099T>C(p.Ile700Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,276,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I700N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000025 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.731

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.120131254).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIAPH1	NM_005219.5	MANE Select	c.2099T>C	p.Ile700Thr	missense	Exon 16 of 28	NP_005210.3
DIAPH1	NM_001079812.3		c.2072T>C	p.Ile691Thr	missense	Exon 15 of 27	NP_001073280.1
DIAPH1	NM_001314007.2		c.2099T>C	p.Ile700Thr	missense	Exon 16 of 29	NP_001300936.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.2099T>C	p.Ile700Thr	missense	Exon 16 of 28	ENSP00000373706.4
DIAPH1	ENST00000518047.5	TSL:5	c.2072T>C	p.Ile691Thr	missense	Exon 15 of 27	ENSP00000428268.2
DIAPH1	ENST00000647433.1		c.2099T>C	p.Ile700Thr	missense	Exon 16 of 29	ENSP00000494675.1

Frequencies

GnomAD3 genomes

AF:

0.0000253

AC:

AN:

118550

Hom.:

Cov.:

show subpopulations

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:

0.0000513

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183574

AF XY:

0.0000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1157462

Hom.:

Cov.:

AF XY:

0.0000106

AC XY:

AN XY:

566990

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25536

American (AMR)

AF:

0.00

AC:

AN:

31212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14184

East Asian (EAS)

AF:

0.00

AC:

AN:

18070

South Asian (SAS)

AF:

0.00

AC:

AN:

74856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4310

European-Non Finnish (NFE)

AF:

0.0000142

AC:

AN:

915086

Other (OTH)

AF:

0.0000471

AC:

AN:

42466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

AF:

0.0000253

AC:

AN:

118550

Hom.:

Cov.:

AF XY:

0.0000178

AC XY:

AN XY:

56310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30822

American (AMR)

AF:

0.00

AC:

AN:

10806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3146

East Asian (EAS)

AF:

0.00

AC:

AN:

3268

South Asian (SAS)

AF:

0.00

AC:

AN:

3052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

200

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

58462

Other (OTH)

AF:

0.00

AC:

AN:

1654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000831

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.10

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.72

M_CAP

Benign

0.019

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

PhyloP100

0.73

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.85

REVEL

Benign

0.13

Sift

Benign

0.070

Sift4G

Uncertain

0.054

Polyphen

0.077

Vest4

0.32

MutPred

0.40

Gain of phosphorylation at I700 (P = 0.0031)

MVP

0.69

MPC

0.15

ClinPred

0.070

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.050

gMVP

0.046

Mutation Taster

=85/15

polymorphism

(source)

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over