11-111993496-A-C

Variant names:

• chr11-111993496-A-C
• NM_001037954.4:c.1273A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001037954.4(DIXDC1):​c.1273A>C​(p.Lys425Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIXDC1 NM_001037954.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

Genes affected

DIXDC1 (HGNC:23695): (DIX domain containing 1) The protein encoded by this gene is a positive regulator of the Wnt signaling pathway. The encoded protein is found associated with gamma tubulin at the centrosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3454528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIXDC1	NM_001037954.4	c.1273A>C	p.Lys425Gln	missense_variant, splice_region_variant	Exon 13 of 20	ENST00000440460.7	NP_001033043.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIXDC1	ENST00000440460.7	c.1273A>C	p.Lys425Gln	missense_variant, splice_region_variant	Exon 13 of 20	1	NM_001037954.4	ENSP00000394352.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1273A>C (p.K425Q) alteration is located in exon 13 (coding exon 13) of the DIXDC1 gene. This alteration results from a A to C substitution at nucleotide position 1273, causing the lysine (K) at amino acid position 425 to be replaced by a glutamine (Q). 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	0.20
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Uncertain	0.61	T
REVEL	Benign	0.083
Sift4G	Benign	0.23	T;T
Polyphen		1.0	D;.
Vest4		0.48
MutPred		0.16		Loss of ubiquitination at K425 (P = 0.011);.;
MVP		0.63
MPC		0.64
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.35
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-111864220;