X-86148774-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053281.3(DACH2):c.154A>G(p.Ser52Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 22)
• Consequence: DACH2 NM_053281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.928

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06547168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACH2	NM_053281.3	c.154A>G	p.Ser52Gly	missense_variant	1/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9	c.154A>G	p.Ser52Gly	missense_variant	1/12	1	NM_053281.3	A2
DACH2	ENST00000373131.5	c.154A>G	p.Ser52Gly	missense_variant	1/12	2		P4
DACH2	ENST00000461604.6	c.154A>G	p.Ser52Gly	missense_variant, NMD_transcript_variant	1/13	5
DACH2	ENST00000506327.6	c.154A>G	p.Ser52Gly	missense_variant, NMD_transcript_variant	1/12	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

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

Jan 18, 2023

The c.154A>G (p.S52G) 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 154, causing the serine (S) at amino acid position 52 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	0.056
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	2.6
Dann	Benign	0.64
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.40	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.32	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.12
Sift	Benign	0.49	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0	B;B
Vest4		0.058
MutPred		0.37		Loss of stability (P = 0.0653);Loss of stability (P = 0.0653);
MVP		0.29
MPC		0.13
ClinPred		0.055	T
GERP RS		2.0
Varity_R		0.045
gMVP		0.44

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-85403778;