NM_005411.5:c.677A>G

Variant names:

• chr10-79614043-A-G
• rs876657999
• NM_005411.5:c.677A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

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 5 ACMG points.

• PM1: In a disulfide_bond (size 91) in uniprot entity SFTA1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005411.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA1	NM_005411.5	c.677A>G	p.Glu226Gly	missense_variant	Exon 6 of 6	ENST00000398636.8	NP_005402.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPA1	ENST00000398636.8	c.677A>G	p.Glu226Gly	missense_variant	Exon 6 of 6	1	NM_005411.5	ENSP00000381633.3
SFTPA1	ENST00000419470.6	c.722A>G	p.Glu241Gly	missense_variant	Exon 6 of 6	1		ENSP00000397082.2
SFTPA1	ENST00000428376.6	c.677A>G	p.Glu226Gly	missense_variant	Exon 5 of 5	1		ENSP00000411102.2
SFTPA1	ENST00000429958.5	c.*203A>G		downstream_gene_variant		1		ENSP00000395527.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.018	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.68
MutPred		0.58		Loss of catalytic residue at E226 (P = 0.073);Loss of catalytic residue at E226 (P = 0.073);.;
MVP		0.78
MPC		2.2
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.74
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs876657999; hg19: chr10-81373799;