chr10-79612431-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_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
NM_005411.5 missense, splice_region
Scores
7
8
3
Splicing: ADA: 0.9988
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;D;.;.;.
Vest4
MutPred
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
MPC
0.14
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at