rs1124

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001317778.2(SFTPC):c.539G>A(p.Ser180Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,612,222 control chromosomes in the GnomAD database, including 80,274 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5934 hom., cov: 34)

Exomes 𝑓: 0.32 ( 74340 hom. )

Consequence

SFTPC
NM_001317778.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.418

Publications

61 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 -18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001317778.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0031855404).

BP6

Variant 8-22164004-G-A is Benign according to our data. Variant chr8-22164004-G-A is described in ClinVar as Benign. ClinVar VariationId is 165212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2 link	c.539G>A	p.Ser180Asn	missense_variant	Exon 5 of 6	ENST00000679463.1	NP_001304707.1	P11686A0A0A0MTC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1 link	c.539G>A	p.Ser180Asn	missense_variant	Exon 5 of 6		NM_001317778.2	ENSP00000505152.1		A0A0A0MTC9

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39861

AN:

152142

Hom.:

5939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.277

Gnomad ASJ

AF:

0.297

Gnomad EAS

AF:

0.336

Gnomad SAS

AF:

0.282

Gnomad FIN

AF:

0.325

Gnomad MID

AF:

0.357

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.285

GnomAD2 exomes

AF:

0.299

AC:

74229

AN:

248638

AF XY:

0.302

show subpopulations

Gnomad AFR exome

AF:

0.104

Gnomad AMR exome

AF:

0.264

Gnomad ASJ exome

AF:

0.308

Gnomad EAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.330

Gnomad NFE exome

AF:

0.332

Gnomad OTH exome

AF:

0.313

GnomAD4 exome

AF:

0.316

AC:

461276

AN:

1459962

Hom.:

74340

Cov.:

AF XY:

0.316

AC XY:

229605

AN XY:

726288

show subpopulations

African (AFR)

AF:

0.103

AC:

3442

AN:

33426

American (AMR)

AF:

0.265

AC:

11853

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8146

AN:

26136

East Asian (EAS)

AF:

0.320

AC:

12702

AN:

39700

South Asian (SAS)

AF:

0.275

AC:

23728

AN:

86192

European-Finnish (FIN)

AF:

0.323

AC:

17106

AN:

53004

Middle Eastern (MID)

AF:

0.305

AC:

1397

AN:

4584

European-Non Finnish (NFE)

AF:

0.328

AC:

364217

AN:

1111960

Other (OTH)

AF:

0.310

AC:

18685

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

20856

41712

62567

83423

104279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11610

23220

34830

46440

58050

<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:

0.262

AC:

39857

AN:

152260

Hom.:

5934

Cov.:

AF XY:

0.262

AC XY:

19533

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.110

AC:

4567

AN:

41584

American (AMR)

AF:

0.276

AC:

4228

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1032

AN:

3470

East Asian (EAS)

AF:

0.336

AC:

1737

AN:

5166

South Asian (SAS)

AF:

0.282

AC:

1359

AN:

4824

European-Finnish (FIN)

AF:

0.325

AC:

3448

AN:

10612

Middle Eastern (MID)

AF:

0.332

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.330

AC:

22464

AN:

67986

Other (OTH)

AF:

0.285

AC:

603

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1502

3004

4507

6009

7511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<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:

0.310

Hom.:

26708

Bravo

AF:

0.254

TwinsUK

AF:

0.322

AC:

1194

ALSPAC

AF:

0.326

AC:

1255

ESP6500AA

AF:

0.105

AC:

432

ESP6500EA

AF:

0.335

AC:

2800

ExAC

AF:

0.298

AC:

36094

Asia WGS

AF:

0.287

AC:

997

AN:

3478

EpiCase

AF:

0.339

EpiControl

AF:

0.336

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: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

0.087

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0082

T;T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.49

T;T;T

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.42

PrimateAI

Benign

0.47

PROVEAN

Benign

0.97

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.42

T;T;T

Sift4G

Benign

0.73

T;T;T

Vest4

0.057

MPC

0.41

ClinPred

0.011

GERP RS

2.3

gMVP

0.58

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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