X-86148634-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_053281.3(DACH2):c.14C>T(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,169,558 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000090 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.0000094 ( 0 hom. 2 hem. )

Consequence

DACH2
NM_053281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036629915).

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.14C>T	p.Ala5Val	missense_variant	1/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9 linkuse as main transcript	c.14C>T	p.Ala5Val	missense_variant	1/12	1	NM_053281.3	A2	Q96NX9-1
DACH2	ENST00000373131.5 linkuse as main transcript	c.14C>T	p.Ala5Val	missense_variant	1/12	2		P4	Q96NX9-2
DACH2	ENST00000461604.6 linkuse as main transcript	c.14C>T	p.Ala5Val	missense_variant, NMD_transcript_variant	1/13	5
DACH2	ENST00000506327.6 linkuse as main transcript	c.14C>T	p.Ala5Val	missense_variant, NMD_transcript_variant	1/12	2

Frequencies

GnomAD3 genomes

AF:

0.0000901

AC:

AN:

110961

Hom.:

Cov.:

AF XY:

0.0000904

AC XY:

AN XY:

33187

show subpopulations

Gnomad AFR

AF:

0.000328

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

GnomAD3 exomes

AF:

0.0000341

AC:

AN:

117399

Hom.:

AF XY:

0.00

AC XY:

AN XY:

31427

show subpopulations

Gnomad AFR exome

AF:

0.000237

Gnomad AMR exome

AF:

0.0000981

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000945

AC:

AN:

1058548

Hom.:

Cov.:

AF XY:

0.00000584

AC XY:

AN XY:

342262

show subpopulations

Gnomad4 AFR exome

AF:

0.000198

Gnomad4 AMR exome

AF:

0.0000680

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:

0.00

Gnomad4 OTH exome

AF:

0.0000674

GnomAD4 genome

AF:

0.0000901

AC:

AN:

111010

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

33246

show subpopulations

Gnomad4 AFR

AF:

0.000327

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

Alfa

AF:

0.000204

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000345

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

Oct 27, 2021

The c.14C>T (p.A5V) alteration is located in exon 1 (coding exon 1) of the DACH2 gene. This alteration results from a C to T substitution at nucleotide position 14, causing the alanine (A) at amino acid position 5 to be replaced by a valine (V). 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

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

1.0

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.14

Sift

Benign

0.054

T;T

Sift4G

Benign

0.18

T;T

Polyphen

0.0010

B;B

Vest4

0.11

MVP

0.40

MPC

0.14

ClinPred

0.041

GERP RS

3.7

Varity_R

0.070

gMVP

0.47

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