rs4715

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 links:

SFTPC (HGNC:):

SFTPC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a propeptide (size 138) in uniprot entity PSPC_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_001317778.2

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 [Likely_benign]. Clinvar id is 165210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-22163524-C-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
SFTPC	NM_001317778.2 linkuse as main transcript	c.413C>A	p.Thr138Asn	missense_variant	4/6	ENST00000679463.1	NP_001304707.1	P11686A0A0A0MTC9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1 linkuse as main transcript	c.413C>A	p.Thr138Asn	missense_variant	4/6		NM_001317778.2	ENSP00000505152.1		A0A0A0MTC9

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

GnomAD3 exomes

AF:

0.252

AC:

62277

AN:

247358

Hom.:

8158

AF XY:

0.255

AC XY:

34246

AN XY:

134386

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 SAS exome

AF:

0.241

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

Gnomad4 AFR exome

AF:

0.0569

Gnomad4 AMR exome

AF:

0.240

Gnomad4 ASJ exome

AF:

0.271

Gnomad4 EAS exome

AF:

0.266

Gnomad4 SAS exome

AF:

0.245

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.268

Gnomad4 OTH exome

AF:

0.259

GnomAD4 genome

AF:

0.211

AC:

32184

AN:

152192

Hom.:

4000

Cov.:

AF XY:

0.214

AC XY:

15936

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0633

Gnomad4 AMR

AF:

0.244

Gnomad4 ASJ

AF:

0.258

Gnomad4 EAS

AF:

0.294

Gnomad4 SAS

AF:

0.254

Gnomad4 FIN

AF:

0.282

Gnomad4 NFE

AF:

0.270

Gnomad4 OTH

AF:

0.238

Alfa

AF:

0.261

Hom.:

11135

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 14735158) -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2013

- -

Interstitial lung disease 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Osteogenesis Imperfecta, Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Pulmonary Surfactant Metabolism Dysfunction, Dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary pulmonary alveolar proteinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2015

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over