12-85280451-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006982.3(ALX1):c.190C>T(p.Arg64Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,611,938 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R64L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 7 hom. )

Consequence

ALX1
NM_006982.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.76

Publications

4 publications found

Variant links:

Genes affected

ALX1 (HGNC:1494): (ALX homeobox 1) The specific function of this gene has yet to be determined in humans; however, in rodents, it is necessary for survival of the forebrain mesenchyme and may also be involved in development of the cervix. Mutations in the mouse gene lead to neural tube defects such as acrania and meroanencephaly. [provided by RefSeq, Jul 2008]

ALX1 Gene-Disease associations (from GenCC):

frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P, ClinGen

ALX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031996757).

BP6

Variant 12-85280451-C-T is Benign according to our data. Variant chr12-85280451-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210133.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006982.3. 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
	ALX1	NM_006982.3	MANE Select	c.190C>T	p.Arg64Cys	missense	Exon 1 of 4	NP_008913.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALX1	ENST00000316824.4	TSL:1 MANE Select	c.190C>T	p.Arg64Cys	missense	Exon 1 of 4	ENSP00000315417.3

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

324

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00199

AC:

497

AN:

249514

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.000437

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00907

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00278

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00279

AC:

4078

AN:

1459722

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1968

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33432

American (AMR)

AF:

0.00119

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

226

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000441

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00112

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00133

AC:

AN:

4524

European-Non Finnish (NFE)

AF:

0.00317

AC:

3522

AN:

1111984

Other (OTH)

AF:

0.00270

AC:

163

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

226

452

679

905

1131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00213

AC:

324

AN:

152216

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

153

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

41528

American (AMR)

AF:

0.00196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00606

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00341

AC:

232

AN:

68012

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00237

Hom.:

Bravo

AF:

0.00208

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00173

AC:

210

EpiCase

AF:

0.00322

EpiControl

AF:

0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Uncertain:1

Jan 14, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALX1-related disorder

Benign:1

Nov 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.083

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.067

MetaRNN

Benign

0.032

MetaSVM

Uncertain

0.43

MutationAssessor

Benign

1.2

PhyloP100

1.8

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.53

Sift

Uncertain

0.0030

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.67

MVP

0.97

MPC

0.57

ClinPred

0.021

GERP RS

4.5

PromoterAI

0.069

Neutral

(source)

Varity_R

0.19

gMVP

0.43

Mutation Taster

=79/21

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