rs876657633

Variant names:

• chr16-2300001-GCACCTT-TGG
• rs876657633
• NM_001089.3:c.1609_1611+4delAAGGTGCinsCCA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001089.3(ABCA3):​c.1609_1611+4delAAGGTGCinsCCA​(p.Lys537del) variant causes a splice donor, conservative inframe deletion, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ABCA3 NM_001089.3 splice_donor, conservative_inframe_deletion, splice_region, synonymous, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.23

Genes affected

ABCA3 (HGNC:33): (ATP binding cassette subfamily A member 3) 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, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. The full transporter encoded by this gene may be involved in development of resistance to xenobiotics and engulfment during programmed cell death. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028152492 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2300001-GCACCTT-TGG is Pathogenic according to our data. Variant chr16-2300001-GCACCTT-TGG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228242.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.1609_1611+4delAAGGTGCinsCCA	p.Lys537del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 13 of 33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.1609_1611+4delAAGGTGCinsCCA	p.Lys537del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 13 of 33	1	NM_001089.3	ENSP00000301732.5
ABCA3	ENST00000382381.7	c.1435_1437+4delAAGGTGCinsCCA	p.Lys479del	splice_donor_variant, conservative_inframe_deletion, splice_region_variant, synonymous_variant, intron_variant	Exon 12 of 32	1		ENSP00000371818.3
ABCA3	ENST00000563623.5	n.2172_2174+4delAAGGTGCinsCCA		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 13 of 20	1

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Diffuse interstitial pulmonary fibrosis;C5680383:Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies Pathogenic:1

Feb 26, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1609_1611+4delinsCCA variant in ABCA3 has been previously reported in 1 co mpound heterozygous individual with interstitial lung disease (Doan 2008, Wambac h 2014). Data from large population studies is insufficient to assess the freque ncy of this variant. This variant removes the last 3 bases of exon 13 along with the highly conserved +1 and +2 positions in the 5' splice site consensus sequen ce, and inserts three new bases. This deletion/insertion variant is expected to disrupt splicing and lead to an abnormal or absent protein. In summary, although additional studies are required to fully establish its clinical significance, t he c.1609_1611+4delinsCCA variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs876657633; hg19: chr16-2350002;