rs1554476282

Positions:

• chr8-22163508-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_001317778.2(SFTPC):​c.397A>C​(p.Ser133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.48

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a propeptide (size 138) in uniprot entity PSPC_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_001317778.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798
• PP5: Variant 8-22163508-A-C is Pathogenic according to our data. Variant chr8-22163508-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521813.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-22163508-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPC	NM_001317778.2	c.397A>C	p.Ser133Arg	missense_variant	4/6	ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1	c.397A>C	p.Ser133Arg	missense_variant	4/6		NM_001317778.2	ENSP00000505152	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2017

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Surfactant metabolism dysfunction, pulmonary, 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;.;T;T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	0.92	D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.95, 0.90	.;.;P;.;P;.;.
Vest4		0.38
MutPred		0.75		Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);.;Gain of solvent accessibility (P = 0.0766);.;.;
MVP		0.83
MPC		1.3
ClinPred		0.98	D
GERP RS		4.3
gMVP		0.87

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: rs1554476282; hg19: chr8-22021021;