1-110064589-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006492.3(ALX3):c.592C>T(p.Gln198Ter) variant causes a stop gained, 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 pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALX3 NM_006492.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9723
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

Genes affected

ALX3 (HGNC:449): (ALX homeobox 3) This gene encodes a nuclear protein with a homeobox DNA-binding domain that functions as a transcriptional regulator involved in cell-type differentiation and development. Preferential methylation of this gene's promoter is associated with advanced-stage neuroblastoma tumors. [provided by RefSeq, Jul 2008]

STRIP1 (HGNC:25916): (striatin interacting protein 1) This gene encodes a member of the striatin-interacting phosphatase and kinase complex, which is involved in localization of the Golgi body. The encoded protein participates in cytosketelal organization. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-110064589-G-A is Pathogenic according to our data. Variant chr1-110064589-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2146917.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX3	NM_006492.3	c.592C>T	p.Gln198Ter	stop_gained, splice_region_variant	2/4	ENST00000647563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX3	ENST00000647563.2	c.592C>T	p.Gln198Ter	stop_gained, splice_region_variant	2/4		NM_006492.3	P1
ALX3	ENST00000649954.1	c.163C>T	p.Gln55Ter	stop_gained, splice_region_variant	1/3
STRIP1	ENST00000473429.5	n.4214-7866G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2022

This sequence change creates a premature translational stop signal (p.Gln198*) in the ALX3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALX3 are known to be pathogenic (PMID: 19409524, 29215096). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALX3-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	48
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A
Vest4		0.98
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.080		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: chr1-110607211; COSMIC: COSV63928570; COSMIC: COSV63928570;