chr2-85666649-G-TTC

Variant names:

• chr2-85666649-G-TTC
• rs35328240
• NM_000542.5:c.361delCinsGAA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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: Genomes: not found (cov: 32)
• Consequence: SFTPB NM_000542.5 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.61
• Publications: 4 publications found

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]

SFTPB Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 13201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	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	P07988
	SFTPB	NM_001367281.1		c.361delCinsGAA	p.Pro121GlufsTer95	frameshift missense	Exon 4 of 9	NP_001354210.1

Ensembl Transcripts

Sel.	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	P07988
	SFTPB	ENST00000393822.7	TSL:1	c.361delCinsGAA	p.Pro121GlufsTer95	frameshift missense	Exon 5 of 12	ENSP00000377409.4	P07988
	SFTPB	ENST00000409383.7	TSL:1	c.361delCinsGAA	p.Pro121GlufsTer95	frameshift missense	Exon 5 of 12	ENSP00000386346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Surfactant metabolism dysfunction, pulmonary, 1 (5)
1	-	-	Hereditary pulmonary alveolar proteinosis (1)
1	-	-	not provided (1)
1	-	-	SFTPB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs35328240; hg19: chr2-85893772;