X-86148753-A-G

Position:

chrX-86148753-A-G

Variant summary

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

The NM_053281.3(DACH2):c.133A>G(p.Ser45Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,209,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000064 ( 0 hom. 41 hem. )

Consequence

DACH2
NM_053281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

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=0.04438448).

BS2

High Hemizygotes in GnomAdExome4 at 41 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACH2	NM_053281.3 linkuse as main transcript	c.133A>G	p.Ser45Gly	missense_variant	1/12	ENST00000373125.9	NP_444511.1	Q96NX9-1A8K3I1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DACH2	ENST00000373125.9 linkuse as main transcript	c.133A>G	p.Ser45Gly	missense_variant	1/12	1	NM_053281.3	ENSP00000362217.4	Q96NX9-1
DACH2	ENST00000373131.5 linkuse as main transcript	c.133A>G	p.Ser45Gly	missense_variant	1/12	2		ENSP00000362223.1	Q96NX9-2
DACH2	ENST00000461604.6 linkuse as main transcript	n.133A>G		non_coding_transcript_exon_variant	1/13	5		ENSP00000421509.1	D6RFG7
DACH2	ENST00000506327.6 linkuse as main transcript	n.133A>G		non_coding_transcript_exon_variant	1/12	2		ENSP00000426837.1	D6REJ4

Frequencies

GnomAD3 genomes

AF:

0.00000902

AC:

AN:

110857

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33059

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:

0.000390

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000136

AC:

AN:

183155

Hom.:

AF XY:

0.000281

AC XY:

AN XY:

67631

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 SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000637

AC:

AN:

1098205

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

363561

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.00000902

AC:

AN:

110857

Hom.:

Cov.:

AF XY:

0.0000302

AC XY:

AN XY:

33059

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:

0.000390

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.000288

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

Sep 05, 2024

The c.133A>G (p.S45G) alteration is located in exon 1 (coding exon 1) of the DACH2 gene. This alteration results from a A to G substitution at nucleotide position 133, causing the serine (S) at amino acid position 45 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

0.073

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;T

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.65

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.044

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.69

N;N

REVEL

Uncertain

0.38

Sift

Uncertain

0.017

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.53

P;P

Vest4

0.13

MutPred

0.49

Loss of stability (P = 0.0385);Loss of stability (P = 0.0385);

MVP

0.84

MPC

0.13

ClinPred

0.088

GERP RS

4.5

Varity_R

0.19

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.

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