dbSNP rs773784830: DACH2:p.Ala285Glu (chrX-86695102-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_053281.3(DACH2):c.854C>A(p.Ala285Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000243 in 1,151,793 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000024 ( 0 hom. 10 hem. )

Consequence

DACH2
NM_053281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.60

Publications

0 publications found

Variant links:

Genes affected

DACH2 (HGNC:16814): (dachshund family transcription factor 2) This gene is one of two genes which encode a protein similar to the Drosophila protein dachshund, a transcription factor involved in cell fate determination in the eye, limb and genital disc of the fly. The encoded protein contains two characteristic dachshund domains: an N-terminal domain responsible for DNA binding and a C-terminal domain responsible for protein-protein interactions. This gene is located on the X chromosome and is subject to inactivation by DNA methylation. The encoded protein may be involved in regulation of organogenesis and myogenesis, and may play a role in premature ovarian failure. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

DACH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10948369).

BS2

High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DACH2	NM_053281.3 link	c.854C>A	p.Ala285Glu	missense_variant	Exon 5 of 12	ENST00000373125.9	NP_444511.1	Q96NX9-1A8K3I1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DACH2	ENST00000373125.9 link	c.854C>A	p.Ala285Glu	missense_variant	Exon 5 of 12	1	NM_053281.3	ENSP00000362217.4		Q96NX9-1

Frequencies

GnomAD3 genomes

AF:

0.0000269

AC:

AN:

111571

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000755

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000560

AC:

AN:

142731

AF XY:

0.0000475

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00104

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000150

Gnomad OTH exome

AF:

0.000307

GnomAD4 exome

AF:

0.0000240

AC:

AN:

1040222

Hom.:

Cov.:

AF XY:

0.0000304

AC XY:

AN XY:

329024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24282

American (AMR)

AF:

0.00

AC:

AN:

28223

Ashkenazi Jewish (ASJ)

AF:

0.000908

AC:

AN:

17630

East Asian (EAS)

AF:

0.00

AC:

AN:

26857

South Asian (SAS)

AF:

0.00

AC:

AN:

43882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3872

European-Non Finnish (NFE)

AF:

0.00000738

AC:

AN:

812629

Other (OTH)

AF:

0.0000689

AC:

AN:

43529

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000269

AC:

AN:

111571

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33739

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30703

American (AMR)

AF:

0.00

AC:

AN:

10517

Ashkenazi Jewish (ASJ)

AF:

0.000755

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3493

South Asian (SAS)

AF:

0.00

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53079

Other (OTH)

AF:

0.00

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.854C>A (p.A285E) alteration is located in exon 5 (coding exon 5) of the DACH2 gene. This alteration results from a C to A substitution at nucleotide position 854, causing the alanine (A) at amino acid position 285 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.18

.;T;.;.;T

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

D;D;D;D;D

M_CAP

Benign

0.057

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

.;L;.;.;.

PhyloP100

3.6

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.1

N;N;N;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.028

D;D;D;D;.

Sift4G

Benign

0.44

T;T;T;T;T

Polyphen

0.32

B;B;.;.;.

Vest4

0.35

MVP

0.52

MPC

0.17

ClinPred

0.14

GERP RS

4.8

Varity_R

0.33

gMVP

0.40

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over