X-86149074-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_053281.3(DACH2):c.454T>C(p.Phe152Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 111,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
• Consequence: DACH2 NM_053281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DACH2	NM_053281.3	c.454T>C	p.Phe152Leu	missense_variant	1/12	ENST00000373125.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DACH2	ENST00000373125.9	c.454T>C	p.Phe152Leu	missense_variant	1/12	1	NM_053281.3	A2
DACH2	ENST00000373131.5	c.454T>C	p.Phe152Leu	missense_variant	1/12	2		P4
DACH2	ENST00000461604.6	c.454T>C	p.Phe152Leu	missense_variant, NMD_transcript_variant	1/13	5
DACH2	ENST00000506327.6	c.454T>C	p.Phe152Leu	missense_variant, NMD_transcript_variant	1/12	2

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111001 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33207

Gnomad AFR AF: 0.0000658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111001 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33207

Gnomad4 AFR AF: 0.0000658

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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 29, 2024

The c.454T>C (p.F152L) alteration is located in exon 1 (coding exon 1) of the DACH2 gene. This alteration results from a T to C substitution at nucleotide position 454, causing the phenylalanine (F) at amino acid position 152 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	27
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.98	D;D
Vest4		0.89
MutPred		0.61		Loss of methylation at K150 (P = 0.1179);Loss of methylation at K150 (P = 0.1179);
MVP		1.0
MPC		0.50
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.62
gMVP		0.96

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: rs1325653538; hg19: chrX-85404078;