8-22161838-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001317778.2(SFTPC):c.10G>A(p.Gly4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.514

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27053148).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPC	NM_001317778.2	c.10G>A	p.Gly4Ser	missense_variant	1/6	ENST00000679463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPC	ENST00000679463.1	c.10G>A	p.Gly4Ser	missense_variant	1/6		NM_001317778.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249386 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000716 Hom.: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Jun 28, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Benign	0.031	T;T;.;T;T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.025	D
MutationTaster	Benign	0.99	N;N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D;N;D;N;D;N;N
REVEL	Benign	0.20
Sift	Benign	0.051	T;T;T;D;T;D;D
Sift4G	Benign	0.087	T;T;T;T;T;T;T
Polyphen		0.20, 0.13	.;.;B;.;B;.;.
Vest4		0.20
MutPred		0.62		Gain of phosphorylation at G4 (P = 0.0126);Gain of phosphorylation at G4 (P = 0.0126);Gain of phosphorylation at G4 (P = 0.0126);Gain of phosphorylation at G4 (P = 0.0126);Gain of phosphorylation at G4 (P = 0.0126);Gain of phosphorylation at G4 (P = 0.0126);Gain of phosphorylation at G4 (P = 0.0126);
MVP		0.90
MPC		0.57
ClinPred		0.13	T
GERP RS		2.1
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201896861; hg19: chr8-22019351; COSMIC: COSV59346175; COSMIC: COSV59346175;