rs11891778

chr2-215045850-G-Achr2-215045850-G-Cchr2-215045850-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_173076.3(ABCA12):c.859C>T(p.Arg287Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,460,760 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ABCA12 NM_173076.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.83

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]

(HGNC:):

ACMG classification

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 2-215045850-G-A is Pathogenic according to our data. Variant chr2-215045850-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 264999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-215045850-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA12	NM_173076.3	c.859C>T	p.Arg287Ter	stop_gained	7/53	ENST00000272895.12
ABCA12	XM_011510951.3	c.859C>T	p.Arg287Ter	stop_gained	7/53
ABCA12	NR_103740.2	n.1301C>T		non_coding_transcript_exon_variant	8/55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA12	ENST00000272895.12	c.859C>T	p.Arg287Ter	stop_gained	7/53	1	NM_173076.3	P1
	ENST00000628464.2	n.1021+1333G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000626134.2	n.404+1333G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000626771.1	n.338+1333G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250144 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135266

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460760 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2019	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30916489, 25525159, 19664001, 29880184) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 16, 2023	This sequence change creates a premature translational stop signal (p.Arg287*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with congenital ichthyosis (PMID: 19664001, 29880184). ClinVar contains an entry for this variant (Variation ID: 264999). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive congenital ichthyosis 4A Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Aug 13, 2018

The observed variant c.859C>T (p.Arg287Ter) has not been reported in 1000 Genomes and ExAC databases. The in silico prediction of the given variant is disease causing by MutationTaster2. -

Autosomal recessive congenital ichthyosis 4B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	44
Dann	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0e-37	P
Vest4		0.90
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: -13

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

Publications

LitVar

Other links and lift over

dbSNP: rs11891778; hg19: chr2-215910574;