rs35328240
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000542.5(SFTPB):c.361delCinsGAA(p.Pro121GlufsTer95) variant causes a frameshift, missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P121A) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000542.5 frameshift, missense
Scores
Clinical Significance
Conservation
Publications
- surfactant metabolism dysfunction, pulmonary, 1Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000542.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SFTPB | NM_000542.5 | MANE Select | c.361delCinsGAA | p.Pro121GlufsTer95 | frameshift missense | Exon 4 of 11 | NP_000533.4 | ||
| SFTPB | NM_198843.3 | c.361delCinsGAA | p.Pro121GlufsTer95 | frameshift missense | Exon 5 of 12 | NP_942140.3 | |||
| SFTPB | NM_001367281.1 | c.361delCinsGAA | p.Pro121GlufsTer95 | frameshift missense | Exon 4 of 9 | NP_001354210.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| SFTPB | ENST00000519937.7 | TSL:1 MANE Select | c.361delCinsGAA | p.Pro121GlufsTer95 | frameshift missense | Exon 4 of 11 | ENSP00000428719.2 | ||
| SFTPB | ENST00000393822.7 | TSL:1 | c.361delCinsGAA | p.Pro121GlufsTer95 | frameshift missense | Exon 5 of 12 | ENSP00000377409.4 | ||
| SFTPB | ENST00000409383.7 | TSL:1 | c.361delCinsGAA | p.Pro121GlufsTer95 | frameshift missense | Exon 5 of 12 | ENSP00000386346.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 35
GnomAD4 genome
ClinVar
Submissions by phenotype
Surfactant metabolism dysfunction, pulmonary, 1 Pathogenic:5
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
Observed in the homozygous state in approximately 70% of individuals with hereditary surfactant protein B deficiency (PMID: 19833825, 8163685); 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; Also known as NM_000542.5:c.361delinsGAA, p.(P121Efs*95); This variant is associated with the following publications: (PMID: 8163685, 21965505, 23625987, 19833825, 7491219, 28965766)
SFTPB-related disorder Pathogenic:1
The SFTPB c.397delinsGAA variant is predicted to result in a frameshift and premature protein termination (p.Pro133Glufs*95). This variant has been reported in the compound heterozygous and homozygous state to be causative for pulmonary alveolar proteinosis and fatal neonatal respiratory insufficiency due to surfactant metabolism dysfunction and surfactant protein B deficiency (Nogee et al. 1994. PubMed ID: 8163685; Ballard et al. 1995. PubMed ID: 7491219; Tredano et al. 1999. PubMed ID: 10571948; Turcu et al. 2013. PubMed ID: 23625987; also known as 121ins2 and c.361delinsGAA (p.Pro121GlufsX95) in literature). Of note, this variant in the heterozygous state was reported in one patient with interstitial lung disease, although other reported c.397delinsGAA heterozygous siblings and parents were completely asymptomatic (Rossi et al. 2011. PubMed ID: 21965505). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in SFTPB are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive SFTPB-related disease.
Hereditary pulmonary alveolar proteinosis Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at