17-8072842-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001139.3(ALOX12B):c.2035C>A(p.Arg679Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R679H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALOX12B NM_001139.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-8072841-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 995721.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 17-8072842-G-T is Pathogenic according to our data. Variant chr17-8072842-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 995720.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALOX12B	NM_001139.3	c.2035C>A	p.Arg679Ser	missense_variant	15/15	ENST00000647874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALOX12B	ENST00000647874.1	c.2035C>A	p.Arg679Ser	missense_variant	15/15		NM_001139.3	P1
ALOX12B	ENST00000649809.1	c.1099C>A	p.Arg367Ser	missense_variant	8/8
ALOX12B	ENST00000650441.1	n.458C>A		non_coding_transcript_exon_variant	4/4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive congenital ichthyosis 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute for Human Genetics, University Medical Center Freiburg

Jan 07, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.34	N
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.7	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.98		Loss of MoRF binding (P = 0.0577);Loss of MoRF binding (P = 0.0577);.;
MVP		0.90
MPC		1.6
ClinPred		1.0	D
GERP RS		2.6
Varity_R		0.98
gMVP		0.98

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

LitVar

Other links and lift over

dbSNP: rs1977008879; hg19: chr17-7976160;