X-86812933-G-A

Variant summary

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

The NM_053281.3(DACH2):c.1318G>A(p.Ala440Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,205,172 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.000051 (0 hom. 17 hem.)
• Consequence: DACH2 NM_053281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.366

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=0.11446336).
• BS2: High Hemizygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACH2	NM_053281.3	c.1318G>A	p.Ala440Thr	missense_variant	8/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9	c.1318G>A	p.Ala440Thr	missense_variant	8/12	1	NM_053281.3	A2

Frequencies

GnomAD3 genomes AF: 0.000135 AC: 15 AN: 111477 Hom.: 0 Cov.: 22 AF XY: 0.0000891 AC XY: 3 AN XY: 33653

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

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: 0.0000188

Gnomad OTH AF: 0.000664

GnomAD3 exomes AF: 0.0000445 AC: 8 AN: 179964 Hom.: 0 AF XY: 0.0000464 AC XY: 3 AN XY: 64596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000541

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000452

GnomAD4 exome AF: 0.0000512 AC: 56 AN: 1093695 Hom.: 0 Cov.: 29 AF XY: 0.0000473 AC XY: 17 AN XY: 359251

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000570

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000358

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.000135 AC: 15 AN: 111477 Hom.: 0 Cov.: 22 AF XY: 0.0000891 AC XY: 3 AN XY: 33653

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.000664

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000165 AC: 2

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

Apr 14, 2023

The c.1318G>A (p.A440T) alteration is located in exon 8 (coding exon 8) of the DACH2 gene. This alteration results from a G to A substitution at nucleotide position 1318, causing the alanine (A) at amino acid position 440 to be replaced by a threonine (T). 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	0.075
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	13
Dann	Benign	0.90
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.51	T;T;T;T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.65	N;N;N;N;.;N
REVEL	Benign	0.13
Sift	Benign	0.048	D;D;T;T;.;D
Sift4G	Benign	0.27	T;T;D;D;D;D
Polyphen		0.052	B;B;.;.;.;.
Vest4		0.12
MutPred		0.36		.;Gain of glycosylation at A440 (P = 0.01);.;.;.;.;
MVP		0.50
MPC		0.13
ClinPred		0.018	T
GERP RS		-2.2
Varity_R		0.069
gMVP		0.15

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

Other links and lift over

dbSNP: rs748352318; hg19: chrX-86067936;