11-111964604-C-T

Variant summary

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

The NM_001037954.4(DIXDC1):c.116C>T(p.Ala39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DIXDC1 NM_001037954.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2392146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIXDC1	NM_001037954.4	c.116C>T	p.Ala39Val	missense_variant	2/20	ENST00000440460.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIXDC1	ENST00000440460.7	c.116C>T	p.Ala39Val	missense_variant	2/20	1	NM_001037954.4	P1
DIXDC1	ENST00000529225.5	c.113C>T	p.Ala38Val	missense_variant	3/6	5
DIXDC1	ENST00000528399.1	n.196C>T		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459376 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725676

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 25, 2022

The c.116C>T (p.A39V) alteration is located in exon 2 (coding exon 2) of the DIXDC1 gene. This alteration results from a C to T substitution at nucleotide position 116, causing the alanine (A) at amino acid position 39 to be replaced by a valine (V). 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	0.092
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	0.028	D
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.20
Sift	Benign	0.093	T;D
Sift4G	Benign	0.081	T;D
Polyphen		0.012	.;B
Vest4		0.31
MutPred		0.39		.;Loss of relative solvent accessibility (P = 0.0676);
MVP		0.93
MPC		0.21
ClinPred		0.71	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.13

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: chr11-111835328;