Variant X-86714701-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_053281.3(DACH2):c.1085C>G(p.Ala362Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000059 in 1,170,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000060 ( 0 hom. 19 hem. )

Consequence

DACH2
NM_053281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.25

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17501083).

BS2

High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACH2	NM_053281.3 linkuse as main transcript	c.1085C>G	p.Ala362Gly	missense_variant	6/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9 linkuse as main transcript	c.1085C>G	p.Ala362Gly	missense_variant	6/12	1	NM_053281.3	A2	Q96NX9-1

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

112044

Hom.:

Cov.:

AF XY:

0.0000877

AC XY:

AN XY:

34214

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000294

AC:

AN:

169954

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

56092

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000404

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:

0.0000518

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1058184

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

332476

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000598

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000254

Gnomad4 NFE exome

AF:

0.0000686

Gnomad4 OTH exome

AF:

0.0000906

GnomAD4 genome

AF:

0.0000536

AC:

AN:

112044

Hom.:

Cov.:

AF XY:

0.0000877

AC XY:

AN XY:

34214

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:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.1085C>G (p.A362G) alteration is located in exon 6 (coding exon 6) of the DACH2 gene. This alteration results from a C to G substitution at nucleotide position 1085, causing the alanine (A) at amino acid position 362 to be replaced by a glycine (G). 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

0.092

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.45

Cadd

Benign

Dann

Uncertain

0.98

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

T;T;T;T;T;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Uncertain

-0.19

MutationTaster

Benign

0.91

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

N;N;N;N;.;N

REVEL

Benign

0.26

Sift

Benign

0.13

T;T;T;T;.;T

Sift4G

Benign

0.30

T;T;T;T;T;T

Polyphen

0.94

P;P;.;.;.;.

Vest4

0.18

MutPred

0.18

.;Loss of stability (P = 0.017);.;.;.;.;

MVP

0.70

MPC

0.14

ClinPred

0.051

GERP RS

4.2

Varity_R

0.25

gMVP

0.48

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over