chr5-141528831-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_005219.5(DIAPH1):ā€‹c.2889A>Gā€‹(p.Ala963Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,138 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 Likely benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.000018 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.891
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 Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.7).
BP6
Variant 5-141528831-T-C is Benign according to our data. Variant chr5-141528831-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.891 with no splicing effect.
BS2
High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DIAPH1NM_005219.5 linkuse as main transcriptc.2889A>G p.Ala963Ala synonymous_variant 22/28 ENST00000389054.8 NP_005210.3 O60610-1Q6URC4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DIAPH1ENST00000389054.8 linkuse as main transcriptc.2889A>G p.Ala963Ala synonymous_variant 22/285 NM_005219.5 ENSP00000373706.4 O60610-1
DIAPH1ENST00000518047.5 linkuse as main transcriptc.2862A>G p.Ala954Ala synonymous_variant 21/275 ENSP00000428268.2 O60610-3
DIAPH1ENST00000647433.1 linkuse as main transcriptc.2889A>G p.Ala963Ala synonymous_variant 22/29 ENSP00000494675.1 A0A2R8Y5N1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152244
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:
0.00
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:
0.0000120
AC:
3
AN:
249280
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135250
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000178
AC:
26
AN:
1461894
Hom.:
0
Cov.:
32
AF XY:
0.0000220
AC XY:
16
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000901
Hom.:
0
Bravo
AF:
0.0000378
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 22, 2015p.Ala963Ala in exon 22 of DIAPH1: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. This variant has been identified in 1/6669 6 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org). -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 18, 2019- -
Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 22, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.70
CADD
Benign
0.40
DANN
Benign
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs770304914; hg19: chr5-140908398; API