rs756003432

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_005219.5(DIAPH1):​c.3358G>A​(p.Glu1120Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E1120E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

2
17

Clinical Significance

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

Conservation

PhyloP100: 0.809
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 made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.100854784).
BS2
High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DIAPH1NM_005219.5 linkc.3358G>A p.Glu1120Lys missense_variant 25/28 ENST00000389054.8 NP_005210.3 O60610-1Q6URC4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DIAPH1ENST00000389054.8 linkc.3358G>A p.Glu1120Lys missense_variant 25/285 NM_005219.5 ENSP00000373706.4 O60610-1
DIAPH1ENST00000518047.5 linkc.3331G>A p.Glu1111Lys missense_variant 24/275 ENSP00000428268.2 O60610-3
DIAPH1ENST00000647433.1 linkc.3358G>A p.Glu1120Lys missense_variant 25/29 ENSP00000494675.1 A0A2R8Y5N1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152142
Hom.:
0
Cov.:
32
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:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249352
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135290
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS 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:
0.00000616
AC:
9
AN:
1461882
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74436
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 20, 2021The c.3358G>A (p.E1120K) alteration is located in exon 25 (coding exon 25) of the DIAPH1 gene. This alteration results from a G to A substitution at nucleotide position 3358, causing the glutamic acid (E) at amino acid position 1120 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 07, 2019This sequence change replaces glutamic acid with lysine at codon 1120 of the DIAPH1 protein (p.Glu1120Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs756003432, ExAC 0.009%) but has not been reported in the literature in individuals with a DIAPH1-related disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.22
T;.;T;.;T;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.23
N
LIST_S2
Uncertain
0.91
D;D;D;D;D;D
M_CAP
Benign
0.0034
T
MetaRNN
Benign
0.10
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.88
L;.;.;.;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.9
.;.;.;N;N;.
REVEL
Benign
0.069
Sift
Benign
0.26
.;.;.;T;T;.
Sift4G
Benign
0.47
T;.;T;T;T;T
Polyphen
0.0040
B;.;.;.;.;.
Vest4
0.14
MutPred
0.53
Gain of methylation at E1120 (P = 0.0601);Gain of methylation at E1120 (P = 0.0601);.;.;Gain of methylation at E1120 (P = 0.0601);.;
MVP
0.50
MPC
0.93
ClinPred
0.18
T
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.081
gMVP
0.13

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756003432; hg19: chr5-140905944; API