5-141572026-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005219.5(DIAPH1):​c.2373C>G​(p.Asp791Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,450 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D791D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.300
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.079061866).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIAPH1NM_005219.5 linkc.2373C>G p.Asp791Glu missense_variant Exon 17 of 28 ENST00000389054.8 NP_005210.3 O60610-1Q6URC4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIAPH1ENST00000389054.8 linkc.2373C>G p.Asp791Glu missense_variant Exon 17 of 28 5 NM_005219.5 ENSP00000373706.4 O60610-1
DIAPH1ENST00000518047.5 linkc.2346C>G p.Asp782Glu missense_variant Exon 16 of 27 5 ENSP00000428268.2 O60610-3
DIAPH1ENST00000647433.1 linkc.2373C>G p.Asp791Glu missense_variant Exon 17 of 29 ENSP00000494675.1 A0A2R8Y5N1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000401
AC:
1
AN:
249570
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461450
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727078
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33468
American (AMR)
AF:
0.0000224
AC:
1
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111620
Other (OTH)
AF:
0.00
AC:
0
AN:
60374
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
17
DANN
Benign
0.62
DEOGEN2
Benign
0.048
T;.;T;.;T;.
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.60
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.73
T;T;T;T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.079
T;T;T;T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.69
N;.;.;.;.;.
PhyloP100
0.30
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
0.52
N;.;.;N;N;N
REVEL
Benign
0.17
Sift
Benign
1.0
T;.;.;T;T;T
Sift4G
Benign
1.0
T;.;T;T;T;T
Polyphen
0.020
B;.;.;.;.;.
Vest4
0.10
MutPred
0.40
Loss of ubiquitination at K786 (P = 0.0747);Loss of ubiquitination at K786 (P = 0.0747);.;.;Loss of ubiquitination at K786 (P = 0.0747);.;
MVP
0.56
MPC
0.57
ClinPred
0.056
T
GERP RS
0.096
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.036
gMVP
0.25
Mutation Taster
=90/10
polymorphism

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

Other links and lift over

dbSNP: rs756608855; hg19: chr5-140951593; API