rs35328240

chr2-85666648-GG-GTTC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000542.5(SFTPB):c.361delinsGAA(p.Pro121GlufsTer95) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFTPB NM_000542.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.61

Genes affected

SFTPB (HGNC:10801): (surfactant protein B) This gene encodes the pulmonary-associated surfactant protein B (SPB), an amphipathic 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. The SPB enhances the rate of spreading and increases the stability of surfactant monolayers in vitro. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 1, also called pulmonary alveolar proteinosis due to surfactant protein B deficiency, and are associated with fatal respiratory distress in the neonatal period. Alternatively spliced transcript variants encoding the same protein have been identified.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-85666649-G-TTC is Pathogenic according to our data. Variant chr2-85666649-G-TTC is described in ClinVar as [Pathogenic]. Clinvar id is 13201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPB	NM_000542.5	c.361delinsGAA	p.Pro121GlufsTer95	frameshift_variant	4/11	ENST00000519937.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPB	ENST00000519937.7	c.361delinsGAA	p.Pro121GlufsTer95	frameshift_variant	4/11	1	NM_000542.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 31, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 04, 2020	This frameshift variant results in a premature stop codon, likely leading to nonsense-mediated decay and lack of protein production. This variant has been reported in numerous infants with respiratory distress and is considered the most common disease-causing SFTPB variant. SFTPB c.361delCinsGAA (rs779795223) is rare (<0.1%) in a large population dataset (gnomAD: 62/282666 total alleles; 0.02%; no homozygotes), and has been reported in ClinVar. We consider this variant to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2022

Observed in the homozygous state in approximately 70% of individuals with hereditary surfactant protein B deficiency (Baekvad-Hansen et al., 2010); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also known as 121ins2; This variant is associated with the following publications: (PMID: 8163685, 23625987, 21965505, 7491219, 19833825) -

Hereditary pulmonary alveolar proteinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2020

The c.397delCinsGAA pathogenic mutation (also known as 121ins2 and c.361delCinsGAA), located in coding exon 4 of the SFTPB gene, results from the deletion of one nucleotide and insertion of 3 nucleotides causing a translational frameshift with a predicted alternate stop codon (p.P133Efs*95). This mutation has been reported in several affected cohorts, and more than two-thirds of patients with surfactant protein B deficiency are carriers of the c.397delCinsGAA mutation (Ballard PL et al. Pediatrics, 1995 Dec;96:1046-52; Turcu S et al. Arch. Dis. Child., 2013 Jul;98:490-5; Kurath-Koller S et al. AJP Rep, 2015 Apr;5:e53-9). This mutation is associated with congenital pulmonary alveolar proteinosis and severe respiratory distress in the neonatal period progressing to respiratory failure (Nogee LM et al. J. Clin. Invest., 1994 Apr;93:1860-3). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35328240; hg19: chr2-85893772;