chrX-86148709-C-T

Position:

• chrX-86148709-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053281.3(DACH2):​c.89C>T​(p.Ser30Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,278 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DACH2 NM_053281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.02

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26379716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DACH2	NM_053281.3	c.89C>T	p.Ser30Leu	missense_variant	1/12	ENST00000373125.9	NP_444511.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DACH2	ENST00000373125.9	c.89C>T	p.Ser30Leu	missense_variant	1/12	1	NM_053281.3	ENSP00000362217.4
DACH2	ENST00000373131.5	c.89C>T	p.Ser30Leu	missense_variant	1/12	2		ENSP00000362223.1
DACH2	ENST00000461604.6	n.89C>T		non_coding_transcript_exon_variant	1/13	5		ENSP00000421509.1
DACH2	ENST00000506327.6	n.89C>T		non_coding_transcript_exon_variant	1/12	2		ENSP00000426837.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097278 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362682

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

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

Mar 20, 2024

The c.89C>T (p.S30L) alteration is located in exon 1 (coding exon 1) of the DACH2 gene. This alteration results from a C to T substitution at nucleotide position 89, causing the serine (S) at amino acid position 30 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.86	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		0.94	P;P
Vest4		0.15
MutPred		0.25		Loss of disorder (P = 0.0315);Loss of disorder (P = 0.0315);
MVP		0.57
MPC		0.16
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.24
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

LitVar

Other links and lift over

dbSNP: rs1602233569; hg19: chrX-85403713;