1-110061017-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006492.3(ALX3):c.748C>G(p.Pro250Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000623 in 1,610,442 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P250L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

ALX3
NM_006492.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.256

Publications

0 publications found

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:

ENSG00000258634 (HGNC:):

ENSG00000258634 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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054830313).

BP6

Variant 1-110061017-G-C is Benign according to our data. Variant chr1-110061017-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00333 (507/152272) while in subpopulation AFR AF = 0.0116 (482/41564). AF 95% confidence interval is 0.0107. There are 3 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX3	NM_006492.3	MANE Select	c.748C>G	p.Pro250Ala	missense	Exon 4 of 4	NP_006483.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALX3	ENST00000647563.2	MANE Select	c.748C>G	p.Pro250Ala	missense	Exon 4 of 4	ENSP00000497310.1
ALX3	ENST00000649954.1		c.319C>G	p.Pro107Ala	missense	Exon 3 of 3	ENSP00000497035.1
ENSG00000258634	ENST00000554749.1	TSL:6	n.2678G>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00333

AC:

506

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000655

AC:

155

AN:

236576

AF XY:

0.000486

show subpopulations

Gnomad AFR exome

AF:

0.0105

Gnomad AMR exome

AF:

0.000237

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000341

AC:

497

AN:

1458170

Hom.:

Cov.:

AF XY:

0.000303

AC XY:

220

AN XY:

725086

show subpopulations

African (AFR)

AF:

0.0128

AC:

429

AN:

33438

American (AMR)

AF:

0.000271

AC:

AN:

44288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000467

AC:

AN:

85690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52646

Middle Eastern (MID)

AF:

0.000380

AC:

AN:

5266

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110972

Other (OTH)

AF:

0.000731

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

110

137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00333

AC:

507

AN:

152272

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

243

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0116

AC:

482

AN:

41564

American (AMR)

AF:

0.000980

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68006

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.00366

ESP6500AA

AF:

0.00923

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000762

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALX3: BP4, BS1; ENSG00000258634: BS1

not specified

Benign:1

Jul 24, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.12

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0055

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.90

PhyloP100

0.26

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.4

REVEL

Benign

0.20

Sift

Benign

0.036

Sift4G

Benign

0.42

Polyphen

0.0040

Vest4

0.069

MVP

0.93

MPC

0.25

ClinPred

0.0056

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.063

gMVP

0.60

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over