NM_005219.5:c.2107C>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.2107C>G(p.Pro703Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,537,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P703Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 21)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 7.32

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: 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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19405854).

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.2107C>G	p.Pro703Ala	missense	Exon 16 of 28	NP_005210.3
DIAPH1	NM_001079812.3		c.2080C>G	p.Pro694Ala	missense	Exon 15 of 27	NP_001073280.1	O60610-3
DIAPH1	NM_001314007.2		c.2107C>G	p.Pro703Ala	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.2107C>G	p.Pro703Ala	missense	Exon 16 of 28	ENSP00000373706.4	O60610-1
DIAPH1	ENST00000518047.5	TSL:5	c.2080C>G	p.Pro694Ala	missense	Exon 15 of 27	ENSP00000428268.2	O60610-3
DIAPH1	ENST00000647433.1		c.2107C>G	p.Pro703Ala	missense	Exon 16 of 29	ENSP00000494675.1	A0A2R8Y5N1

Frequencies

GnomAD3 genomes

AF:

0.000143

AC:

AN:

147096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000502

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:

0.000271

Gnomad OTH

AF:

0.000504

GnomAD2 exomes

AF:

0.000169

AC:

AN:

189262

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.0000812

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:

0.000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000132

AC:

184

AN:

1390110

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

100

AN XY:

685832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31958

American (AMR)

AF:

0.00

AC:

AN:

38684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22222

East Asian (EAS)

AF:

0.00

AC:

AN:

37106

South Asian (SAS)

AF:

0.0000253

AC:

AN:

78914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49460

Middle Eastern (MID)

AF:

0.000184

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

0.000163

AC:

174

AN:

1069414

Other (OTH)

AF:

0.000123

AC:

AN:

56910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.587

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:

0.000143

AC:

AN:

147096

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

AN XY:

71608

show subpopulations

African (AFR)

AF:

0.0000502

AC:

AN:

39842

American (AMR)

AF:

0.00

AC:

AN:

14804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

4868

South Asian (SAS)

AF:

0.00

AC:

AN:

4376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000271

AC:

AN:

66494

Other (OTH)

AF:

0.000504

AC:

AN:

1984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

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:

0.000285

Hom.:

ExAC

AF:

0.000149

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

0.10

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.29

Eigen

Benign

-0.086

Eigen_PC

Benign

-0.079

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.62

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.1

PhyloP100

7.3

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.35

Sift

Benign

0.12

Sift4G

Uncertain

0.0080

Polyphen

0.0030

Vest4

0.46

MutPred

0.61

Loss of glycosylation at P703 (P = 0.0025)

MVP

0.78

MPC

0.11

ClinPred

0.11

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.033

gMVP

0.12

Mutation Taster

=72/28

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