chr16-2317661-A-C

Variant names:

• chr16-2317661-A-C
• rs121909185
• NM_001089.3:c.977T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001089.3(ABCA3):​c.977T>G​(p.Leu326Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L326P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.61
• Publications: 3 publications found

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]

ABCA3 Gene-Disease associations (from GenCC):

• interstitial lung disease due to ABCA3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001089.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	NM_001089.3	MANE Select	c.977T>G	p.Leu326Arg	missense	Exon 9 of 33	NP_001080.2	Q99758-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.977T>G	p.Leu326Arg	missense	Exon 9 of 33	ENSP00000301732.5	Q99758-1
	ABCA3	ENST00000382381.7	TSL:1	c.977T>G	p.Leu326Arg	missense	Exon 9 of 32	ENSP00000371818.3	H0Y3H2
	ABCA3	ENST00000563623.5	TSL:1	n.1540T>G		non_coding_transcript_exon	Exon 9 of 20

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		Gain of methylation at L326 (P = 0.0197)
MVP		0.99
MPC		1.0
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.96
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs121909185; hg19: chr16-2367662;