rs1124

Variant names:

• chr8-22164004-G-A
• rs1124
• NM_001317778.2:c.539G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_003018.4(SFTPC):​c.557G>A​(p.Ser186Asn) 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_003018.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.418
• Publications: 61 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):

• 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

ACMG classification

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_003018.4
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003018.4. 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.539G>A	p.Ser180Asn	missense	Exon 5 of 6	NP_001304707.1
	SFTPC	NM_001172410.2		c.557G>A	p.Ser186Asn	missense	Exon 5 of 6	NP_001165881.1
	SFTPC	NM_001385653.1		c.557G>A	p.Ser186Asn	missense	Exon 5 of 6	NP_001372582.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPC	ENST00000679463.1	MANE Select	c.539G>A	p.Ser180Asn	missense	Exon 5 of 6	ENSP00000505152.1
	SFTPC	ENST00000318561.7	TSL:1	c.557G>A	p.Ser186Asn	missense	Exon 5 of 6	ENSP00000316152.3
	SFTPC	ENST00000521315.5	TSL:1	c.539G>A	p.Ser180Asn	missense	Exon 5 of 5	ENSP00000430410.1

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39861 AN: 152142 Hom.: 5939 Cov.: 34

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

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.: 50 AF XY: 0.316 AC XY: 229605 AN XY: 726288

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

GnomAD4 genome AF: 0.262 AC: 39857 AN: 152260 Hom.: 5934 Cov.: 34 AF XY: 0.262 AC XY: 19533 AN XY: 74448

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: 97 AN: 292

European-Non Finnish (NFE) AF: 0.330 AC: 22464 AN: 67986

Other (OTH) AF: 0.285 AC: 603 AN: 2114

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

ClinVar submissions as Germline

Significance: 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	0.087
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.42
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.97	N
REVEL	Benign	0.12
Sift	Benign	0.42	T
Sift4G	Benign	0.73	T
Vest4		0.057
MPC		0.41
ClinPred		0.011	T
GERP RS		2.3
gMVP		0.58
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1124; hg19: chr8-22021517; COSMIC: COSV59345528; COSMIC: COSV59345528;