Genetic Variant NM_005411.5:c.135C>A (chr10-79611960-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005411.5(SFTPA1):c.135C>A(p.Asp45Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D45D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SFTPA1
NM_005411.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0870

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPA1	NM_005411.5 link	c.135C>A	p.Asp45Glu	missense_variant	Exon 3 of 6	ENST00000398636.8	NP_005402.3	Q8IWL2-1A0A024QZP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPA1	ENST00000398636.8 link	c.135C>A	p.Asp45Glu	missense_variant	Exon 3 of 6	1	NM_005411.5	ENSP00000381633.3		Q8IWL2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250682

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461586

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111788

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.098

T;T;.;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.88

.;D;D;.;D

M_CAP

Benign

0.0052

MetaRNN

Uncertain

0.45

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.;.;.

PhyloP100

-0.087

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.85

N;N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.020

D;D;D;D;D

Sift4G

Benign

0.71

T;T;T;T;T

Polyphen

1.0

D;D;.;.;.

Vest4

0.40

MutPred

0.27

Gain of methylation at R47 (P = 0.1084);Gain of methylation at R47 (P = 0.1084);.;Gain of methylation at R47 (P = 0.1084);Gain of methylation at R47 (P = 0.1084);

MVP

0.31

MPC

0.13

ClinPred

0.94

GERP RS

-2.5

Varity_R

0.083

gMVP

0.24

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_005411.5:c.135C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over