rs121917834

Variant names:

• chr8-22163096-T-C
• rs121917834
• NM_001317778.2:c.218T>C
• SFTPC p.Ile73Thr

Your query was ambiguous. Multiple possible variants found:

• chr8-22163096-T-C
• chr8-22163096-T-A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PM2 PP5_Very_Strong

The NM_001317778.2(SFTPC):​c.218T>C​(p.Ile73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002058361: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:21092132)."" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 2.22
• Publications: 130 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: Orphanet, ClinGen
• surfactant metabolism dysfunction, pulmonary, 2

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002058361: "Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 21092132)."; SCV002231594: Experimental studies have shown that this missense change affects SFTPC function (PMID: 21707890).; SCV005325092: "Published functional studies demonstrate damaging effects including impaired uptake and degradation of surfactant phospholipid and accumulation of dysfunctional mitochondria." PMID: 21707890, 25344067; SCV002725353: "In vitro studies have demonstrated that this alteration interferes with correct processing and routing of the final protein, as well as reduction in lipid degradation (Beers, 2011)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001317778.2
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-22163096-T-C is Pathogenic according to our data. Variant chr8-22163096-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.218T>C	p.Ile73Thr	missense	Exon 3 of 6	NP_001304707.1	P11686-2
	SFTPC	NM_001172410.2		c.218T>C	p.Ile73Thr	missense	Exon 3 of 6	NP_001165881.1	A0A0S2Z4Q0
	SFTPC	NM_001385653.1		c.218T>C	p.Ile73Thr	missense	Exon 3 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.218T>C	p.Ile73Thr	missense	Exon 3 of 6	ENSP00000505152.1	P11686-2
	SFTPC	ENST00000318561.7	TSL:1	c.218T>C	p.Ile73Thr	missense	Exon 3 of 6	ENSP00000316152.3	P11686-1
	SFTPC	ENST00000521315.5	TSL:1	c.218T>C	p.Ile73Thr	missense	Exon 3 of 5	ENSP00000430410.1	P11686-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249478 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461844 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Surfactant metabolism dysfunction, pulmonary, 2 (9)
3	-	-	not provided (3)
1	-	-	Hereditary pulmonary alveolar proteinosis (1)
-	-	-	Pulmonary fibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	0.91	D
PhyloP100		2.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121917834;

hg19: chr8-22020609;