17-8076742-A-G

Variant names:

• chr17-8076742-A-G
• rs137853023
• NM_001139.3:c.1277T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001139.3(ALOX12B):​c.1277T>C​(p.Leu426Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALOX12B NM_001139.3 missense, splice_region
• Scores: Splicing: ADA: 0.1689
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.28
• Publications: 3 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001139.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-8076742-A-G is Pathogenic according to our data. Variant chr17-8076742-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6083.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1277T>C	p.Leu426Pro	missense splice_region	Exon 10 of 15	NP_001130.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALOX12B	ENST00000647874.1	MANE Select	c.1277T>C	p.Leu426Pro	missense splice_region	Exon 10 of 15	ENSP00000497784.1
	ALOX12B	ENST00000649809.1		c.341T>C	p.Leu114Pro	missense splice_region	Exon 3 of 8	ENSP00000496845.1
	ALOX12B	ENST00000577351.5	TSL:5	n.224T>C		splice_region non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397950 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 689488

African (AFR) AF: 0.00 AC: 0 AN: 31554

American (AMR) AF: 0.00 AC: 0 AN: 35712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35756

South Asian (SAS) AF: 0.00 AC: 0 AN: 79180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4374

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079004

Other (OTH) AF: 0.00 AC: 0 AN: 57892

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 2 Pathogenic:2

Jan 07, 2021

Institute for Human Genetics, University Medical Center Freiburg

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Loss of stability (P = 0.009)
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.97
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.17
dbscSNV1_RF	Benign	0.37
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137853023; hg19: chr17-7980060;