NM_001317778.2:c.413C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001317778.2(SFTPC):c.413C>A(p.Thr138Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,610,828 control chromosomes in the GnomAD database, including 54,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T138T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.21 ( 4000 hom., cov: 33)

Exomes 𝑓: 0.26 ( 50754 hom. )

Consequence

SFTPC
NM_001317778.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.960

Publications

55 publications found

Variant links:

Genes affected

SFTPC (HGNC:10802): (surfactant protein C) This gene encodes the pulmonary-associated surfactant protein C (SPC), an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 2, also called pulmonary alveolar proteinosis due to surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and adults. Alternatively spliced transcript variants encoding different protein isoforms have been identified.[provided by RefSeq, Feb 2010]

SFTPC Gene-Disease associations (from GenCC):

surfactant metabolism dysfunction, pulmonary, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
chronic respiratory distress with surfactant metabolism deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
SFTPC- related interstitial lung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SFTPC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027724802).

BP6

Variant 8-22163524-C-A is Benign according to our data. Variant chr8-22163524-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2 link	c.413C>A	p.Thr138Asn	missense_variant	Exon 4 of 6	ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1 link	c.413C>A	p.Thr138Asn	missense_variant	Exon 4 of 6		NM_001317778.2	ENSP00000505152.1

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32190

AN:

152070

Hom.:

4003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0633

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.258

Gnomad EAS

AF:

0.293

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.282

Gnomad MID

AF:

0.322

Gnomad NFE

AF:

0.270

Gnomad OTH

AF:

0.238

GnomAD2 exomes

AF:

0.252

AC:

62277

AN:

247358

AF XY:

0.255

show subpopulations

Gnomad AFR exome

AF:

0.0577

Gnomad AMR exome

AF:

0.240

Gnomad ASJ exome

AF:

0.269

Gnomad EAS exome

AF:

0.280

Gnomad FIN exome

AF:

0.280

Gnomad NFE exome

AF:

0.273

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.260

AC:

379934

AN:

1458636

Hom.:

50754

Cov.:

AF XY:

0.261

AC XY:

189629

AN XY:

725740

show subpopulations

African (AFR)

AF:

0.0569

AC:

1901

AN:

33438

American (AMR)

AF:

0.240

AC:

10740

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

7083

AN:

26114

East Asian (EAS)

AF:

0.266

AC:

10567

AN:

39682

South Asian (SAS)

AF:

0.245

AC:

21083

AN:

86176

European-Finnish (FIN)

AF:

0.275

AC:

14608

AN:

53150

Middle Eastern (MID)

AF:

0.261

AC:

1504

AN:

5762

European-Non Finnish (NFE)

AF:

0.268

AC:

296813

AN:

1109312

Other (OTH)

AF:

0.259

AC:

15635

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

15424

30848

46271

61695

77119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9764

19528

29292

39056

48820

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.211

AC:

32184

AN:

152192

Hom.:

4000

Cov.:

AF XY:

0.214

AC XY:

15936

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0633

AC:

2629

AN:

41554

American (AMR)

AF:

0.244

AC:

3727

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.258

AC:

896

AN:

3470

East Asian (EAS)

AF:

0.294

AC:

1514

AN:

5158

South Asian (SAS)

AF:

0.254

AC:

1223

AN:

4822

European-Finnish (FIN)

AF:

0.282

AC:

2985

AN:

10592

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.270

AC:

18354

AN:

67990

Other (OTH)

AF:

0.238

AC:

501

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1270

2541

3811

5082

6352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

338

676

1014

1352

1690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.253

Hom.:

23082

Bravo

AF:

0.203

TwinsUK

AF:

0.262

AC:

970

ALSPAC

AF:

0.258

AC:

995

ESP6500AA

AF:

0.0621

AC:

241

ESP6500EA

AF:

0.274

AC:

2277

ExAC

AF:

0.251

AC:

30281

Asia WGS

AF:

0.253

AC:

878

AN:

3478

EpiCase

AF:

0.281

EpiControl

AF:

0.277

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 14735158) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jun 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Interstitial lung disease 2

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Osteogenesis Imperfecta, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pulmonary Surfactant Metabolism Dysfunction, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pulmonary alveolar proteinosis

Benign:1

Oct 26, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Surfactant metabolism dysfunction, pulmonary, 2

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;T;.;T;T;T;T

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.62

T;T;T;T;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.96

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.7

D;N;D;D;D;D;D

REVEL

Benign

0.26

Sift

Benign

0.051

T;D;D;D;D;T;T

Sift4G

Benign

0.072

T;T;T;T;T;T;T

Polyphen

0.0020, 0.90

.;.;B;.;P;.;.

Vest4

0.27

MPC

1.2

ClinPred

0.023

GERP RS

2.5

gMVP

0.82

Mutation Taster

=96/4

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over