rs7592

Variant names:

• chr8-22164370-G-A
• rs7592
• NM_001317778.2:c.*123G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001317778.2(SFTPC):​c.*123G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 1,535,018 control chromosomes in the GnomAD database, including 84,777 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9680 hom., cov: 35)
  • Exomes 𝑓: 0.33 (75097 hom.)
• Consequence: SFTPC NM_001317778.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.108
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-22164370-G-A is Benign according to our data. Variant chr8-22164370-G-A is described in ClinVar as Benign. ClinVar VariationId is 362568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPC	NM_001317778.2	c.*123G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000679463.1	NP_001304707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPC	ENST00000679463.1	c.*123G>A		3_prime_UTR_variant	Exon 6 of 6		NM_001317778.2	ENSP00000505152.1

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53794 AN: 152090 Hom.: 9668 Cov.: 35

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.351

GnomAD2 exomes AF: 0.317 AC: 43123 AN: 136128 AF XY: 0.313

Gnomad AFR exome AF: 0.439

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.311

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.325

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.328 AC: 453522 AN: 1382810 Hom.: 75097 Cov.: 45 AF XY: 0.327 AC XY: 222990 AN XY: 682330

African (AFR) AF: 0.433 AC: 13650 AN: 31510

American (AMR) AF: 0.290 AC: 10280 AN: 35446

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 7841 AN: 25130

East Asian (EAS) AF: 0.320 AC: 11422 AN: 35732

South Asian (SAS) AF: 0.277 AC: 21941 AN: 79166

European-Finnish (FIN) AF: 0.319 AC: 10797 AN: 33826

Middle Eastern (MID) AF: 0.323 AC: 1840 AN: 5690

European-Non Finnish (NFE) AF: 0.330 AC: 356341 AN: 1078460

Other (OTH) AF: 0.336 AC: 19410 AN: 57850

GnomAD4 genome AF: 0.354 AC: 53839 AN: 152208 Hom.: 9680 Cov.: 35 AF XY: 0.352 AC XY: 26178 AN XY: 74410

African (AFR) AF: 0.423 AC: 17582 AN: 41532

American (AMR) AF: 0.312 AC: 4774 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1032 AN: 3468

East Asian (EAS) AF: 0.336 AC: 1739 AN: 5168

South Asian (SAS) AF: 0.284 AC: 1370 AN: 4830

European-Finnish (FIN) AF: 0.325 AC: 3446 AN: 10602

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22731 AN: 67992

Other (OTH) AF: 0.350 AC: 740 AN: 2112

Alfa AF: 0.341 Hom.: 14614

Bravo AF: 0.360

Asia WGS AF: 0.306 AC: 1065 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Interstitial lung disease 2 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pulmonary Surfactant Metabolism Dysfunction, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Osteogenesis Imperfecta, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Surfactant metabolism dysfunction, pulmonary, 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.1
DANN	Benign	0.72
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7592; hg19: chr8-22021883; COSMIC: COSV59244657; COSMIC: COSV59244657;