Genetic Variant DIAPH1:p.Asp423Glu (chr5-141577486-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005219.5(DIAPH1):c.1269C>A(p.Asp423Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,178 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D423A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

1 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: ClinGen, Orphanet
autosomal dominant nonsyndromic hearing loss 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
progressive microcephaly-seizures-cortical blindness-developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

DIAPH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIAPH1	NM_005219.5 link	c.1269C>A	p.Asp423Glu	missense_variant	Exon 12 of 28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DIAPH1	ENST00000389054.8 link	c.1269C>A	p.Asp423Glu	missense_variant	Exon 12 of 28	5	NM_005219.5	ENSP00000373706.4
DIAPH1	ENST00000518047.5 link	c.1242C>A	p.Asp414Glu	missense_variant	Exon 11 of 27	5		ENSP00000428268.2
DIAPH1	ENST00000647433.1 link	c.1269C>A	p.Asp423Glu	missense_variant	Exon 12 of 29			ENSP00000494675.1
DIAPH1	ENST00000523100.5 link	n.*496C>A		downstream_gene_variant		5		ENSP00000428208.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249516

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109578

Other (OTH)

AF:

0.00

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Cov.:

ExAC

AF:

0.00000828

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;D;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.87

D;D;D;D;D;D

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.72

D;D;D;D;D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.

PhyloP100

2.0

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.6

D;.;.;D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;.;.;D;D;D

Sift4G

Benign

0.12

T;.;D;T;T;T

Vest4

0.38

ClinPred

0.96

GERP RS

4.1

Varity_R

0.75

gMVP

0.35

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over