NM_001317778.2:c.413C>A

Variant names:

• chr8-22163524-C-A
• rs4715
• NM_001317778.2:c.413C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.960
• Publications: 55 publications found

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):

• SFTPC-related interstitial lung disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• surfactant metabolism dysfunction, pulmonary, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• chronic respiratory distress with surfactant metabolism deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317778.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	NM_001317778.2	MANE Select	c.413C>A	p.Thr138Asn	missense	Exon 4 of 6	NP_001304707.1	P11686-2
	SFTPC	NM_001172410.2		c.413C>A	p.Thr138Asn	missense	Exon 4 of 6	NP_001165881.1	A0A0S2Z4Q0
	SFTPC	NM_001385653.1		c.413C>A	p.Thr138Asn	missense	Exon 4 of 6	NP_001372582.1	P11686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	ENST00000679463.1	MANE Select	c.413C>A	p.Thr138Asn	missense	Exon 4 of 6	ENSP00000505152.1	P11686-2
	SFTPC	ENST00000318561.7	TSL:1	c.413C>A	p.Thr138Asn	missense	Exon 4 of 6	ENSP00000316152.3	P11686-1
	SFTPC	ENST00000521315.5	TSL:1	c.413C>A	p.Thr138Asn	missense	Exon 4 of 5	ENSP00000430410.1	P11686-2

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

GnomAD2 exomes AF: 0.252 AC: 62277 AN: 247358 AF XY: 0.255

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

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

GnomAD4 genome AF: 0.211 AC: 32184 AN: 152192 Hom.: 4000 Cov.: 33 AF XY: 0.214 AC XY: 15936 AN XY: 74396

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: 89 AN: 294

European-Non Finnish (NFE) AF: 0.270 AC: 18354 AN: 67990

Other (OTH) AF: 0.238 AC: 501 AN: 2106

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	Interstitial lung disease 2 (1)
-	-	1	not specified (1)
-	-	1	Osteogenesis Imperfecta, Recessive (1)
-	-	1	Pulmonary Surfactant Metabolism Dysfunction, Dominant (1)
-	-	1	Surfactant metabolism dysfunction, pulmonary, 2 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.96
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.26
Sift	Benign	0.051	T
Sift4G	Benign	0.072	T
Polyphen		0.0020	B
Vest4		0.27
MPC		1.2
ClinPred		0.023	T
GERP RS		2.5
gMVP		0.82
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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