X-86695135-C-T

Position:

• chrX-86695135-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_053281.3(DACH2):​c.887C>T​(p.Ala296Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000692 in 1,011,364 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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: not found (cov: 22)
  • Exomes 𝑓: 0.0000069 (0 hom. 4 hem.)
• Consequence: DACH2 NM_053281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23147556).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACH2	NM_053281.3	c.887C>T	p.Ala296Val	missense_variant	5/12	ENST00000373125.9	NP_444511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DACH2	ENST00000373125.9	c.887C>T	p.Ala296Val	missense_variant	5/12	1	NM_053281.3	ENSP00000362217.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000692 AC: 7 AN: 1011364 Hom.: 0 Cov.: 30 AF XY: 0.0000128 AC XY: 4 AN XY: 313204

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000877

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.887C>T (p.A296V) alteration is located in exon 5 (coding exon 5) of the DACH2 gene. This alteration results from a C to T substitution at nucleotide position 887, causing the alanine (A) at amino acid position 296 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	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T;.;.;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.23	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.0	.;L;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.56	N;N;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.15	T;D;D;T;.
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.80	P;P;.;.;.
Vest4		0.20
MutPred		0.19		.;Loss of disorder (P = 0.0496);.;.;.;
MVP		0.67
MPC		0.14
ClinPred		0.16	T
GERP RS		4.1
Varity_R		0.063
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs766301515; hg19: chrX-85950138; COSMIC: COSV64165756;