rs876657633

Positions:

• chr16-2300000-GGCACCTT-GTGG

Variant summary

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

The ENST00000301732.10(ABCA3):​c.1609_1611+4delinsCCA variant causes a splice donor, splice donor region, coding sequence, 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 ENST00000301732.10 splice_donor, splice_donor_region, coding_sequence, 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 0.027956989 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/exons	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.1609_1611+4delinsCCA		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	13/33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.1609_1611+4delinsCCA		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	13/33	1	NM_001089.3	ENSP00000301732	P1
ABCA3	ENST00000382381.7	c.1435_1437+4delinsCCA		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	12/32	1		ENSP00000371818
ABCA3	ENST00000563623.5	n.2172_2174+4delinsCCA		splice_donor_variant, splice_donor_region_variant, non_coding_transcript_exon_variant, intron_variant	13/20	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

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;