10-79612431-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005411.5(SFTPA1):c.292G>A(p.Gly98Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFTPA1 NM_005411.5 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

Genes affected

SFTPA1 (HGNC:10798): (surfactant protein A1) This gene encodes a lung surfactant protein that is a member of a subfamily of C-type lectins called collectins. The encoded protein binds specific carbohydrate moieties found on lipids and on the surface of microorganisms. This protein plays an essential role in surfactant homeostasis and in the defense against respiratory pathogens. Mutations in this gene are associated with idiopathic pulmonary fibrosis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA1	NM_005411.5	c.292G>A	p.Gly98Arg	missense_variant, splice_region_variant	4/6	ENST00000398636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA1	ENST00000398636.8	c.292G>A	p.Gly98Arg	missense_variant, splice_region_variant	4/6	1	NM_005411.5	P1
SFTPA1	ENST00000419470.6	c.337G>A	p.Gly113Arg	missense_variant, splice_region_variant	4/6	1
SFTPA1	ENST00000428376.6	c.292G>A	p.Gly98Arg	missense_variant, splice_region_variant	3/5	1		P1
SFTPA1	ENST00000429958.5	c.292G>A	p.Gly98Arg	missense_variant, splice_region_variant	3/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Proximal 16p11.2 microdeletion syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Jan 08, 2020

This variant is currently absent from large population controls, patient databases, and the medical literature (Genome Aggregation Database [GnomAD], ClinVar, HGMD). The c.292G>A change is in the last nucleotide (3' end) of exon 4 (NM_005411.4, total 6 exons). It is predicted to substitute the glycine at position 98 with arginine within the collagen-like domain of the protein. Its possible impact on splicing is unknown. In silico splice site prediction tools predict this change will affect splicing, but there is currently no functional data to support these predictions (Human Splicing Finder, Transcript Inferred Pathogenicity Score). This nucleotide position is semi-conserved across species (GERP 2.73) and the p.Gly98Arg change is predicted to be damaging by multiple in silico missense prediction tools (MutationTaster, MutationAssessor, FATHMM, SIFT). There is emerging evidence to support SFTPA1 pathogenic variantsas a rare cause of familial idiopathic pulmonary fibrosis and idiopathic interstitial pneumonia (PMID: 30854216, 26792177, 29977744, 31601679). All pathogenic sequencing variants reported to date have been missense changes. Both autosomal dominant with incomplete penetrance and recessive inheritance models have been proposed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;D;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.55	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H;.;.;.
MutationTaster	Benign	0.70	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.62
MutPred		0.83		Gain of solvent accessibility (P = 0.0063);Gain of solvent accessibility (P = 0.0063);.;Gain of solvent accessibility (P = 0.0063);Gain of solvent accessibility (P = 0.0063);
MVP		0.98
MPC		0.14
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.57
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1589239722; hg19: chr10-81372187;