chr1-110061475-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_006492.3(ALX3):c.683A>G(p.Tyr228Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,884 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
ALX3
NM_006492.3 missense
NM_006492.3 missense
Scores
10
4
Clinical Significance
Conservation
PhyloP100: 2.40
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]
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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;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALX3 | NM_006492.3 | c.683A>G | p.Tyr228Cys | missense_variant | 3/4 | ENST00000647563.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALX3 | ENST00000647563.2 | c.683A>G | p.Tyr228Cys | missense_variant | 3/4 | NM_006492.3 | P1 | ||
ENST00000554749.1 | n.3136T>C | non_coding_transcript_exon_variant | 1/1 | ||||||
ALX3 | ENST00000649954.1 | c.254A>G | p.Tyr85Cys | missense_variant | 2/3 | ||||
STRIP1 | ENST00000473429.5 | n.4213+6673T>C | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 2AN: 152198Hom.: 0 Cov.: 33 FAILED QC
GnomAD3 genomes
?
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33
FAILED QC
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251460Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
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GnomAD4 exome AF: 0.0000267 AC: 39AN: 1461884Hom.: 1 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727246
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74344
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Data not reliable, filtered out with message: AS_VQSR
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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 | Jul 14, 2022 | The c.683A>G (p.Y228C) alteration is located in exon 3 (coding exon 3) of the ALX3 gene. This alteration results from a A to G substitution at nucleotide position 683, causing the tyrosine (Y) at amino acid position 228 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
P;P;.
Vest4
0.30
MutPred
Loss of phosphorylation at Y228 (P = 0.029);Loss of phosphorylation at Y228 (P = 0.029);.;
MVP
0.97
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at