X-86148628-T-C

Variant summary

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

The NM_053281.3(DACH2):ā€‹c.8T>Cā€‹(p.Val3Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000057 in 1,053,037 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 22)
Exomes š‘“: 0.0000057 ( 0 hom. 2 hem. )

Consequence

DACH2
NM_053281.3 missense

Scores

5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.549
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]

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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=0.07318759).
BS2
High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DACH2NM_053281.3 linkc.8T>C p.Val3Ala missense_variant 1/12 ENST00000373125.9 NP_444511.1 Q96NX9-1A8K3I1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DACH2ENST00000373125.9 linkc.8T>C p.Val3Ala missense_variant 1/121 NM_053281.3 ENSP00000362217.4 Q96NX9-1
DACH2ENST00000373131.5 linkc.8T>C p.Val3Ala missense_variant 1/122 ENSP00000362223.1 Q96NX9-2
DACH2ENST00000461604.6 linkn.8T>C non_coding_transcript_exon_variant 1/135 ENSP00000421509.1 D6RFG7
DACH2ENST00000506327.6 linkn.8T>C non_coding_transcript_exon_variant 1/122 ENSP00000426837.1 D6REJ4

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD3 exomes
AF:
0.00000893
AC:
1
AN:
112007
Hom.:
0
AF XY:
0.0000334
AC XY:
1
AN XY:
29965
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000110
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:
0.00000570
AC:
6
AN:
1053037
Hom.:
0
Cov.:
30
AF XY:
0.00000589
AC XY:
2
AN XY:
339527
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000180
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000226
GnomAD4 genome
Cov.:
22

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 submitterclinical testingAmbry GeneticsApr 12, 2024The c.8T>C (p.V3A) alteration is located in exon 1 (coding exon 1) of the DACH2 gene. This alteration results from a T to C substitution at nucleotide position 8, causing the valine (V) at amino acid position 3 to be replaced by an alanine (A). 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
0.23
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.10
.;T
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.67
T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.073
T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
0.69
N;N
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
-0.15
N;N
REVEL
Benign
0.19
Sift
Uncertain
0.0080
D;D
Sift4G
Benign
0.088
T;T
Polyphen
0.0090
B;B
Vest4
0.13
MutPred
0.12
Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);
MVP
0.55
MPC
0.17
ClinPred
0.054
T
GERP RS
3.4
Varity_R
0.076
gMVP
0.40

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.

Other links and lift over

dbSNP: rs1464622104; hg19: chrX-85403632; COSMIC: COSV105927251; API