rs72842957

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001139.3(ALOX12B):c.379C>T(p.Pro127Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,613,950 control chromosomes in the GnomAD database, including 384 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. P127L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 38 hom., cov: 31)

Exomes 𝑓: 0.019 ( 346 hom. )

Consequence

ALOX12B
NM_001139.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.60

Publications

13 publications found

Variant links:

Genes affected

ALOX12B (HGNC:430): (arachidonate 12-lipoxygenase, 12R type) This gene encodes an enzyme involved in the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid. Mutations in this gene are associated with nonbullous congenital ichthyosiform erythroderma. [provided by RefSeq, Sep 2015]

ALOX12B Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
self-healing collodion baby
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ALOX12B links:

ENSG00000214999 (HGNC:):

ENSG00000214999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 70 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Trascript score misZ: 1.7573 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive congenital ichthyosis 2, self-healing collodion baby, congenital non-bullous ichthyosiform erythroderma, lamellar ichthyosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.0051826537).

BP6

Variant 17-8081161-G-A is Benign according to our data. Variant chr17-8081161-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.015 (2278/152188) while in subpopulation AMR AF = 0.0201 (308/15300). AF 95% confidence interval is 0.0183. There are 38 homozygotes in GnomAd4. There are 1086 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001139.3. 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
	ALOX12B	NM_001139.3	MANE Select	c.379C>T	p.Pro127Ser	missense	Exon 3 of 15	NP_001130.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALOX12B	ENST00000647874.1	MANE Select	c.379C>T	p.Pro127Ser	missense	Exon 3 of 15	ENSP00000497784.1
ENSG00000214999	ENST00000399413.3	TSL:1	n.1400G>A		non_coding_transcript_exon	Exon 2 of 2
ENSG00000214999	ENST00000763133.1		n.55-33G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2277

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.0907

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0137

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0176

AC:

4418

AN:

251072

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.0149

Gnomad ASJ exome

AF:

0.0835

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0124

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0188

AC:

27467

AN:

1461762

Hom.:

346

Cov.:

AF XY:

0.0189

AC XY:

13725

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00370

AC:

124

AN:

33480

American (AMR)

AF:

0.0172

AC:

770

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0842

AC:

2200

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0157

AC:

1351

AN:

86258

European-Finnish (FIN)

AF:

0.0130

AC:

694

AN:

53326

Middle Eastern (MID)

AF:

0.0496

AC:

286

AN:

5768

European-Non Finnish (NFE)

AF:

0.0185

AC:

20528

AN:

1111978

Other (OTH)

AF:

0.0250

AC:

1511

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1718

3436

5153

6871

8589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

796

1592

2388

3184

3980

<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:

0.0150

AC:

2278

AN:

152188

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1086

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00395

AC:

164

AN:

41532

American (AMR)

AF:

0.0201

AC:

308

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0907

AC:

315

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5166

South Asian (SAS)

AF:

0.0139

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0121

AC:

128

AN:

10590

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0180

AC:

1227

AN:

67988

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0188

Hom.:

130

Bravo

AF:

0.0158

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0227

AC:

195

ExAC

AF:

0.0171

AC:

2080

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0218

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Autosomal recessive congenital ichthyosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0052

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.7

REVEL

Uncertain

0.33

Sift

Benign

0.10

Sift4G

Uncertain

0.035

Polyphen

0.62

Vest4

0.046

MPC

0.70

ClinPred

0.040

GERP RS

4.1

Varity_R

0.22

gMVP

0.46

Mutation Taster

=83/17

polymorphism (auto)

(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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over