rs199503269

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_173076.3(ABCA12):c.7444C>T(p.Arg2482Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000155 in 1,613,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ABCA12
NM_173076.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.73

Variant links:

Genes affected

ABCA12 (HGNC:14637): (ATP binding cassette subfamily A member 12) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ABCA12 links:

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

SNHG31 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-214937608-G-A is Pathogenic according to our data. Variant chr2-214937608-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 419453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214937608-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA12	NM_173076.3 linkuse as main transcript	c.7444C>T	p.Arg2482Ter	stop_gained	51/53	ENST00000272895.12
SNHG31	NR_110292.1 linkuse as main transcript	n.322-10217G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA12	ENST00000272895.12 linkuse as main transcript	c.7444C>T	p.Arg2482Ter	stop_gained	51/53	1	NM_173076.3	P1	Q86UK0-1
SNHG31	ENST00000670391.1 linkuse as main transcript	n.438-24202G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250934

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460996

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	The R2482X pathogenic variant in the ABCA12 gene has been reported previously with another ABCA12 variant in association with harlequin ichthyosis (Akiyama et al., 2007; Koocheck et al., 2014). In one of these patients, immunostaining of a skin biopsy demonstrated complete loss of ABCA12 expression in the epidermis (Akiyama et al., 2007). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R2482X variant is observed in 1/9,838 (0.01%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). We interpret R2482X as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 15, 2023	This sequence change creates a premature translational stop signal (p.Arg2482*) in the ABCA12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA12 are known to be pathogenic (PMID: 20672373). This variant is present in population databases (rs199503269, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with congenital ichthyosis (PMID: 17684380, 28851938, 31168818). ClinVar contains an entry for this variant (Variation ID: 419453). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive congenital ichthyosis 4B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 15, 2022	A homozygous nonsense variation in exon 51 of the ABCA12 gene that results in a stop codon and premature truncation of the protein at codon 2482 was detected. The observed variation has previously been reported in patients with Herlequin ichthyosis (PMID:17684380). The variant has a minor allele frequency of 0.02% in the 1000 genomes database. The reference region is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 05, 2016	- -

Lamellar ichthyosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 27, 2022

Variant summary: ABCA12 c.7444C>T (p.Arg2482X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 250934 control chromosomes. c.7444C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with features of Lamellar Ichthyosis/Harlequin Ichthyosis (example, Sakai_2009, Khalili_2019, Cho_2017, Kun-Darbois_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.65

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A

Vest4

0.77

GERP RS

4.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over