rs1124

Positions:

chr8-22164004-G-A

Variant summary

Our verdict is Benign. Variant got -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. 14/18 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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 id is 165212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-22164004-G-A is described in Lovd as [Benign].

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/exons	MANE	UniProt
SFTPC	NM_001317778.2 linkuse as main transcript	c.539G>A	p.Ser180Asn	missense_variant	5/6	ENST00000679463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPC	ENST00000679463.1 linkuse as main transcript	c.539G>A	p.Ser180Asn	missense_variant	5/6		NM_001317778.2	A1

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

GnomAD3 exomes

AF:

0.299

AC:

74229

AN:

248638

Hom.:

11540

AF XY:

0.302

AC XY:

40797

AN XY:

135132

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 SAS exome

AF:

0.271

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

Gnomad4 AFR exome

AF:

0.103

Gnomad4 AMR exome

AF:

0.265

Gnomad4 ASJ exome

AF:

0.312

Gnomad4 EAS exome

AF:

0.320

Gnomad4 SAS exome

AF:

0.275

Gnomad4 FIN exome

AF:

0.323

Gnomad4 NFE exome

AF:

0.328

Gnomad4 OTH exome

AF:

0.310

GnomAD4 genome

AF:

0.262

AC:

39857

AN:

152260

Hom.:

5934

Cov.:

AF XY:

0.262

AC XY:

19533

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.276

Gnomad4 ASJ

AF:

0.297

Gnomad4 EAS

AF:

0.336

Gnomad4 SAS

AF:

0.282

Gnomad4 FIN

AF:

0.325

Gnomad4 NFE

AF:

0.330

Gnomad4 OTH

AF:

0.285

Alfa

AF:

0.318

Hom.:

12366

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

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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

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

0.087

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

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

MutationTaster

Benign

0.63

P;P;P;P;P;P

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

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

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