2-85666653-G-T

Variant names:

• chr2-85666653-G-T
• rs368293273
• NM_000542.5:c.357C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000542.5(SFTPB):​c.357C>A​(p.Tyr119*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y119Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFTPB NM_000542.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.333
• Publications: 0 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: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

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.357C>A	p.Tyr119*	stop_gained	Exon 4 of 11	NP_000533.4
	SFTPB	NM_198843.3		c.357C>A	p.Tyr119*	stop_gained	Exon 5 of 12	NP_942140.3
	SFTPB	NM_001367281.1		c.357C>A	p.Tyr119*	stop_gained	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.357C>A	p.Tyr119*	stop_gained	Exon 4 of 11	ENSP00000428719.2
	SFTPB	ENST00000393822.7	TSL:1	c.357C>A	p.Tyr119*	stop_gained	Exon 5 of 12	ENSP00000377409.4
	SFTPB	ENST00000409383.7	TSL:1	c.357C>A	p.Tyr119*	stop_gained	Exon 5 of 12	ENSP00000386346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.47	N
PhyloP100		0.33
Vest4		0.88
ClinPred		0.69	D
GERP RS		0.34
Mutation Taster		=39/161	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs368293273; hg19: chr2-85893776;