rs121917834

Positions:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The NM_001317778.2(SFTPC):​c.218T>A​(p.Ile73Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I73T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SFTPC NM_001317778.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.22

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 Uncertain_significance. Variant got 0 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPC	NM_001317778.2	c.218T>A	p.Ile73Asn	missense_variant	3/6	ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1	c.218T>A	p.Ile73Asn	missense_variant	3/6		NM_001317778.2	ENSP00000505152	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000361 AC: 9 AN: 249478 Hom.: 0 AF XY: 0.0000443 AC XY: 6 AN XY: 135366

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000501

Gnomad SAS 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: 0.00000547 AC: 8 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000331 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	T;T;.;D;D;T;D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	0.96	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;N;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.97, 0.90	.;.;D;.;P;.;.
Vest4		0.67
MutPred		0.70		Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);Gain of disorder (P = 0.0051);.;Gain of disorder (P = 0.0051);.;.;
MVP		1.0
MPC		1.7
ClinPred		0.46	T
GERP RS		4.7
gMVP		0.92

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: rs121917834; hg19: chr8-22020609;