rs4715

chr8-22163524-C-Achr8-22163524-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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 (★★). 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.960

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a propeptide (size 138) in uniprot entity PSPC_HUMAN there are 36 pathogenic changes around while only 7 benign (84%) 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	UniProt
SFTPC	NM_001317778.2	c.413C>A	p.Thr138Asn	missense_variant	4/6	ENST00000679463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPC	ENST00000679463.1	c.413C>A	p.Thr138Asn	missense_variant	4/6		NM_001317778.2	A1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32190 AN: 152070 Hom.: 4003 Cov.: 33

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

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.: 33 AF XY: 0.261 AC XY: 189629 AN XY: 725740

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.: 33 AF XY: 0.214 AC XY: 15936 AN XY: 74396

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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	Invitae	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

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	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
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	N
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	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs4715; hg19: chr8-22021037; COSMIC: COSV59345520; COSMIC: COSV59345520;