Genetic Variant SFTPA1:p.Glu226Gly (chr10-79614043-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_005411.5(SFTPA1):c.677A>G(p.Glu226Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SFTPA1
NM_005411.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.03

Publications

0 publications found

Variant links:

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]

SFTPA1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005411.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SFTPA1	NM_005411.5	MANE Select	c.677A>G	p.Glu226Gly	missense	Exon 6 of 6	NP_005402.3
SFTPA1	NM_001093770.3		c.722A>G	p.Glu241Gly	missense	Exon 6 of 6	NP_001087239.2
SFTPA1	NM_001164644.2		c.677A>G	p.Glu226Gly	missense	Exon 6 of 6	NP_001158116.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SFTPA1	ENST00000398636.8	TSL:1 MANE Select	c.677A>G	p.Glu226Gly	missense	Exon 6 of 6	ENSP00000381633.3
SFTPA1	ENST00000419470.6	TSL:1	c.722A>G	p.Glu241Gly	missense	Exon 6 of 6	ENSP00000397082.2
SFTPA1	ENST00000428376.6	TSL:1	c.677A>G	p.Glu226Gly	missense	Exon 5 of 5	ENSP00000411102.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 02, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu241Gly variant in SFTPA1 has not been previously reported in individual s with pulmonary disease or in large population studies. Computational predictio n tools and conservation analysis suggest that the p.Glu241Gly variant may impac t the protein, though this information is not predictive enough to determine pat hogenicity. In summary, the clinical significance of the p.Glu241Gly variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.9

PhyloP100

5.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.34

Sift

Uncertain

0.018

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.68

MutPred

0.58

Loss of catalytic residue at E226 (P = 0.073)

MVP

0.78

MPC

2.2

ClinPred

1.0

GERP RS

2.9

Varity_R

0.74

gMVP

0.93

Mutation Taster

=41/59

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over