X-86149017-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_053281.3(DACH2):c.397G>A(p.Gly133Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000654 in 1,208,078 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000068 (0 hom. 25 hem.)
• Consequence: DACH2 NM_053281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• BS2: High Hemizygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACH2	NM_053281.3	c.397G>A	p.Gly133Arg	missense_variant	1/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9	c.397G>A	p.Gly133Arg	missense_variant	1/12	1	NM_053281.3	A2
DACH2	ENST00000373131.5	c.397G>A	p.Gly133Arg	missense_variant	1/12	2		P4
DACH2	ENST00000461604.6	c.397G>A	p.Gly133Arg	missense_variant, NMD_transcript_variant	1/13	5
DACH2	ENST00000506327.6	c.397G>A	p.Gly133Arg	missense_variant, NMD_transcript_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.0000360 AC: 4 AN: 110989 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33153

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000285

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000879 AC: 16 AN: 181960 Hom.: 0 AF XY: 0.0000449 AC XY: 3 AN XY: 66852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000440

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: 0.0000494

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000684 AC: 75 AN: 1097089 Hom.: 0 Cov.: 31 AF XY: 0.0000690 AC XY: 25 AN XY: 362499

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000569

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: 0.0000571

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.0000360 AC: 4 AN: 110989 Hom.: 0 Cov.: 22 AF XY: 0.0000302 AC XY: 1 AN XY: 33153

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000285

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000613 Hom.: 2

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

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 27, 2023

The c.397G>A (p.G133R) alteration is located in exon 1 (coding exon 1) of the DACH2 gene. This alteration results from a G to A substitution at nucleotide position 397, causing the glycine (G) at amino acid position 133 to be replaced by an arginine (R). 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	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	28
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.093	T;T
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.74		Gain of MoRF binding (P = 0.0174);Gain of MoRF binding (P = 0.0174);
MVP		0.95
MPC		0.67
ClinPred		0.57	D
GERP RS		3.6
Varity_R		0.64
gMVP		0.97

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: rs201644507; hg19: chrX-85404021; COSMIC: COSV100912838;