rs1003389476

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_005219.5(DIAPH1):​c.3157G>T​(p.Glu1053Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., cov: 25)
Exomes 𝑓: 0.00016 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

DIAPH1
NM_005219.5 stop_gained

Scores

5
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25
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_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DIAPH1NM_005219.5 linkuse as main transcriptc.3157G>T p.Glu1053Ter stop_gained 24/28 ENST00000389054.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DIAPH1ENST00000389054.8 linkuse as main transcriptc.3157G>T p.Glu1053Ter stop_gained 24/285 NM_005219.5 A2O60610-1
DIAPH1ENST00000518047.5 linkuse as main transcriptc.3130G>T p.Glu1044Ter stop_gained 23/275 P4O60610-3
DIAPH1ENST00000647433.1 linkuse as main transcriptc.3157G>T p.Glu1053Ter stop_gained 24/29 A2

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
1
AN:
111228
Hom.:
0
Cov.:
25
FAILED QC
Gnomad AFR
AF:
0.0000352
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.000156
AC:
96
AN:
614992
Hom.:
0
Cov.:
28
AF XY:
0.000132
AC XY:
42
AN XY:
318734
show subpopulations
Gnomad4 AFR exome
AF:
0.0000722
Gnomad4 AMR exome
AF:
0.0000838
Gnomad4 ASJ exome
AF:
0.0000760
Gnomad4 EAS exome
AF:
0.0000976
Gnomad4 SAS exome
AF:
0.000126
Gnomad4 FIN exome
AF:
0.0000271
Gnomad4 NFE exome
AF:
0.000188
Gnomad4 OTH exome
AF:
0.0000780
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000899
AC:
1
AN:
111260
Hom.:
0
Cov.:
25
AF XY:
0.00
AC XY:
0
AN XY:
51520
show subpopulations
Gnomad4 AFR
AF:
0.0000352
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
42
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.98
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;A;A
Vest4
0.89
GERP RS
5.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1003389476; hg19: chr5-140907256; API