NM_173076.3:c.5012dupA

Variant names:

• chr2-214978431-A-AT
• NM_173076.3:c.5012dupA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_173076.3(ABCA12):​c.5012dupA​(p.Asn1671LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA12 NM_173076.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.201

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 2-214978431-A-AT is Pathogenic according to our data. Variant chr2-214978431-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 2803236.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3	c.5012dupA	p.Asn1671LysfsTer2	frameshift_variant	Exon 33 of 53	ENST00000272895.12	NP_775099.2
ABCA12	NM_015657.4	c.4058dupA	p.Asn1353LysfsTer2	frameshift_variant	Exon 25 of 45		NP_056472.2
ABCA12	XM_011510951.3	c.5021dupA	p.Asn1674LysfsTer2	frameshift_variant	Exon 33 of 53		XP_011509253.1
ABCA12	NR_103740.2	n.5510dupA		non_coding_transcript_exon_variant	Exon 35 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12	c.5012dupA	p.Asn1671LysfsTer2	frameshift_variant	Exon 33 of 53	1	NM_173076.3	ENSP00000272895.7
ABCA12	ENST00000389661.4	c.4058dupA	p.Asn1353LysfsTer2	frameshift_variant	Exon 25 of 45	1		ENSP00000374312.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn1671Lysfs*2) 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 variant has not been reported in the literature in individuals affected with ABCA12-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-215843155;