chr1-110060767-T-G

Position:

chr1-110060767-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BS1_Supporting

The NM_006492.3(ALX3):c.998A>C(p.Lys333Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,500,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000084 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

ALX3
NM_006492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.34

Variant links:

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]

ALX3 links:

(HGNC:):

links:

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]

STRIP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.816

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000552 (75/1357618) while in subpopulation SAS AF= 0.000482 (30/62292). AF 95% confidence interval is 0.000346. There are 0 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALX3	NM_006492.3 linkuse as main transcript	c.998A>C	p.Lys333Thr	missense_variant	4/4	ENST00000647563.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ALX3	ENST00000647563.2 linkuse as main transcript	c.998A>C	p.Lys333Thr	missense_variant	4/4		NM_006492.3	P1
	ENST00000554749.1 linkuse as main transcript	n.2428T>G		non_coding_transcript_exon_variant	1/1
ALX3	ENST00000649954.1 linkuse as main transcript	c.569A>C	p.Lys190Thr	missense_variant	3/3
STRIP1	ENST00000473429.5 linkuse as main transcript	n.4213+5965T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000840

AC:

AN:

142934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00239

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000456

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000686

AC:

AN:

247906

Hom.:

AF XY:

0.0000820

AC XY:

AN XY:

134072

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000721

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000299

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000552

AC:

AN:

1357618

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

669702

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00117

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000482

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000566

Gnomad4 OTH exome

AF:

0.000163

GnomAD4 genome

AF:

0.0000839

AC:

AN:

143046

Hom.:

Cov.:

AF XY:

0.0000862

AC XY:

AN XY:

69638

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00239

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000457

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000153

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000676

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2023

The c.998A>C (p.K333T) alteration is located in exon 4 (coding exon 4) of the ALX3 gene. This alteration results from a A to C substitution at nucleotide position 998, causing the lysine (K) at amino acid position 333 to be replaced by a threonine (T). 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

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

Polyphen

1.0

D;D;.

Vest4

0.75

MVP

0.98

MPC

1.0

ClinPred

0.88

GERP RS

4.9

Varity_R

0.77

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over