12-85280452-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006982.3(ALX1):c.191G>T(p.Arg64Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00617 in 1,611,802 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts 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. R64C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 39 hom. )

Consequence

ALX1
NM_006982.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.82

Publications

12 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01105988).

BP6

Variant 12-85280452-G-T is Benign according to our data. Variant chr12-85280452-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALX1	NM_006982.3 link	c.191G>T	p.Arg64Leu	missense_variant	Exon 1 of 4	ENST00000316824.4	NP_008913.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALX1	ENST00000316824.4 link	c.191G>T	p.Arg64Leu	missense_variant	Exon 1 of 4	1	NM_006982.3	ENSP00000315417.3

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

626

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00445

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00353

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00670

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00432

AC:

1076

AN:

249354

AF XY:

0.00444

show subpopulations

Gnomad AFR exome

AF:

0.00119

Gnomad AMR exome

AF:

0.00316

Gnomad ASJ exome

AF:

0.00189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00250

Gnomad NFE exome

AF:

0.00696

Gnomad OTH exome

AF:

0.00475

GnomAD4 exome

AF:

0.00638

AC:

9316

AN:

1459628

Hom.:

Cov.:

AF XY:

0.00619

AC XY:

4497

AN XY:

726108

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33426

American (AMR)

AF:

0.00306

AC:

137

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00176

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00273

AC:

235

AN:

86186

European-Finnish (FIN)

AF:

0.00229

AC:

121

AN:

52728

Middle Eastern (MID)

AF:

0.00714

AC:

AN:

4480

European-Non Finnish (NFE)

AF:

0.00756

AC:

8402

AN:

1111990

Other (OTH)

AF:

0.00508

AC:

306

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

564

1128

1692

2256

2820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.00410

AC:

624

AN:

152174

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

295

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

41510

American (AMR)

AF:

0.00445

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00332

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00669

AC:

455

AN:

68012

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

145

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:

0.00571

Hom.:

Bravo

AF:

0.00440

TwinsUK

AF:

0.00539

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00709

AC:

ExAC

AF:

0.00428

AC:

520

EpiCase

AF:

0.00692

EpiControl

AF:

0.00723

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALX1: BS2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Frontonasal dysplasia - severe microphthalmia - severe facial clefting syndrome

Benign:2

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 03, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

May 02, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALX1-related disorder

Benign:1

Apr 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.080

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.42

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.059

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

1.2

PhyloP100

3.8

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.68

Sift

Uncertain

0.020

Sift4G

Benign

0.65

Vest4

0.63

ClinPred

0.035

GERP RS

5.5

PromoterAI

0.066

Neutral

(source)

Varity_R

0.29

gMVP

0.44

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over