Genetic Variant SFTPB:p.Arg236Ser (chr2-85663814-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_000542.5(SFTPB):c.706C>A(p.Arg236Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SFTPB
NM_000542.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.19

Publications

0 publications found

Variant links:

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)

SFTPB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-85663814-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13204.

BP4

Computational evidence support a benign effect (MetaRNN=0.24174011).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPB	NM_000542.5 link	c.706C>A	p.Arg236Ser	missense_variant	Exon 7 of 11	ENST00000519937.7	NP_000533.4	P07988D6W5L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SFTPB	ENST00000519937.7 link	c.706C>A	p.Arg236Ser	missense_variant	Exon 7 of 11	1	NM_000542.5	ENSP00000428719.2	P07988
SFTPB	ENST00000393822.7 link	c.706C>A	p.Arg236Ser	missense_variant	Exon 8 of 12	1		ENSP00000377409.4	P07988
SFTPB	ENST00000409383.7 link	c.706C>A	p.Arg236Ser	missense_variant	Exon 8 of 12	1		ENSP00000386346.2	P07988
SFTPB	ENST00000428225.5 link	c.694C>A	p.Arg232Ser	missense_variant	Exon 7 of 11	2		ENSP00000415347.1	H0Y7V6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1443828

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33200

American (AMR)

AF:

0.00

AC:

AN:

42720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

38914

South Asian (SAS)

AF:

0.0000238

AC:

AN:

83934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105504

Other (OTH)

AF:

0.00

AC:

AN:

59700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.068

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.64

.;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.24

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.0

L;L;.

PhyloP100

4.2

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.32

.;.;N

REVEL

Benign

0.28

Sift

Benign

0.22

.;.;T

Sift4G

Uncertain

0.035

D;D;D

Polyphen

0.050

B;B;B

Vest4

0.32

MutPred

0.52

.;.;Gain of glycosylation at R248 (P = 0.0902);

MVP

0.87

MPC

0.30

ClinPred

0.73

GERP RS

4.4

PromoterAI

-0.0016

Neutral

(source)

Varity_R

0.18

gMVP

0.35

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over