rs200606811

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_005219.5(DIAPH1):c.2158C>T(p.Leu720Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000093 in 1,602,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 27)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.972

Publications

2 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: Orphanet, ClinGen
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

DIAPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03889391).

BP6

Variant 5-141573692-G-A is Benign according to our data. Variant chr5-141573692-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450432.

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	UniProt
DIAPH1	NM_005219.5	MANE Select	c.2158C>T	p.Leu720Phe	missense	Exon 16 of 28	NP_005210.3
DIAPH1	NM_001079812.3		c.2131C>T	p.Leu711Phe	missense	Exon 15 of 27	NP_001073280.1	O60610-3
DIAPH1	NM_001314007.2		c.2158C>T	p.Leu720Phe	missense	Exon 16 of 29	NP_001300936.1	A0A2R8Y5N1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIAPH1	ENST00000389054.8	TSL:5 MANE Select	c.2158C>T	p.Leu720Phe	missense	Exon 16 of 28	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5	TSL:5	c.2131C>T	p.Leu711Phe	missense	Exon 15 of 27	ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1		c.2158C>T	p.Leu720Phe	missense	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes

AF:

0.000398

AC:

AN:

150856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000594

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000125

AC:

AN:

239424

AF XY:

0.0000692

show subpopulations

Gnomad AFR exome

AF:

0.000950

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000464

Gnomad OTH exome

AF:

0.000510

GnomAD4 exome

AF:

0.0000606

AC:

AN:

1451106

Hom.:

Cov.:

AF XY:

0.0000583

AC XY:

AN XY:

720510

show subpopulations

African (AFR)

AF:

0.000782

AC:

AN:

33262

American (AMR)

AF:

0.000345

AC:

AN:

43512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25740

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000226

AC:

AN:

1104522

Other (OTH)

AF:

0.000250

AC:

AN:

59922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000404

AC:

AN:

150976

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

AN XY:

73714

show subpopulations

African (AFR)

AF:

0.00117

AC:

AN:

41124

American (AMR)

AF:

0.000593

AC:

AN:

15184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5056

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10440

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67670

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.000152

Hom.:

ESP6500AA

AF:

0.000525

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000911

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.66

M_CAP

Benign

0.053

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.97

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.3

REVEL

Benign

0.070

Sift

Benign

0.28

Sift4G

Benign

0.13

Polyphen

0.012

Vest4

0.24

MVP

0.67

MPC

0.12

ClinPred

0.011

GERP RS

2.5

Varity_R

0.074

gMVP

0.038

Mutation Taster

=92/8

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

Computational scores

Splicing

Publications

Other links and lift over