1-110060903-G-A

Variant summary

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

The NM_006492.3(ALX3):c.862C>T(p.Pro288Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALX3 NM_006492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.45

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]

(HGNC:):

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 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=0.15660387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX3	NM_006492.3	c.862C>T	p.Pro288Ser	missense_variant	4/4	ENST00000647563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALX3	ENST00000647563.2	c.862C>T	p.Pro288Ser	missense_variant	4/4		NM_006492.3	P1
	ENST00000554749.1	n.2564G>A		non_coding_transcript_exon_variant	1/1
ALX3	ENST00000649954.1	c.433C>T	p.Pro145Ser	missense_variant	3/3
STRIP1	ENST00000473429.5	n.4213+6101G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 04, 2020

The c.862C>T (p.P288S) alteration is located in coding exon 4 of the ALX3 gene. This alteration results from a C to T substitution at nucleotide position 862, causing the proline (P) at amino acid position 288 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the ALX3 c.862C>T alteration was not observed, with coverage at this position. This amino acid position is not well conserved in available vertebrate species. The p.P288S alteration is predicted to be tolerated by in silico analysis. 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	0.066
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	0.90	D
PrimateAI	Uncertain	0.50	T
Polyphen		0.30	B;B;.
Vest4		0.11
MutPred		0.18		Gain of glycosylation at P288 (P = 0.0322);Gain of glycosylation at P288 (P = 0.0322);.;
MVP		0.95
MPC		0.92
ClinPred		0.59	D
GERP RS		5.2
Varity_R		0.091
gMVP		0.56

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: rs866030551; hg19: chr1-110603525;