rs137853202

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_000542.5(SFTPB):c.706C>T(p.Arg236Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000432 in 1,596,014 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R236R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

SFTPB
NM_000542.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.19

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 2-85663814-G-A is Pathogenic according to our data. Variant chr2-85663814-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13204.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPB	NM_000542.5 link	c.706C>T	p.Arg236Cys	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>T	p.Arg236Cys	missense_variant	Exon 7 of 11	1	NM_000542.5	ENSP00000428719.2	P07988
SFTPB	ENST00000393822.7 link	c.706C>T	p.Arg236Cys	missense_variant	Exon 8 of 12	1		ENSP00000377409.4	P07988
SFTPB	ENST00000409383.7 link	c.706C>T	p.Arg236Cys	missense_variant	Exon 8 of 12	1		ENSP00000386346.2	P07988
SFTPB	ENST00000428225.5 link	c.694C>T	p.Arg232Cys	missense_variant	Exon 7 of 11	2		ENSP00000415347.1	H0Y7V6

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000287

AC:

AN:

209002

AF XY:

0.00000872

show subpopulations

Gnomad AFR exome

AF:

0.000326

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000625

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1443826

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

717098

show subpopulations

African (AFR)

AF:

0.000482

AC:

AN:

33200

American (AMR)

AF:

0.00

AC:

AN:

42720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38914

South Asian (SAS)

AF:

0.00

AC:

AN:

83932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48808

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

1105504

Other (OTH)

AF:

0.0000335

AC:

AN:

59700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000434

AC:

AN:

41448

American (AMR)

AF:

0.0000654

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000459

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Surfactant metabolism dysfunction, pulmonary, 1

Pathogenic:2

Dec 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 04, 2022

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SFTPB c.706C>T has been identified in multiple individuals with surfactant protein B (SP-B) deficiency. This SFTPB variant (rs137853202) is rare (<0.1%) in a large population dataset (gnomAD: 11/240328 total alleles; 0.004577%; one homozygote) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging. The arginine residue at this position is not highly evolutionarily conserved across the species assessed. We consider SFTPB c.706C>T to be pathogenic. -

Hereditary pulmonary alveolar proteinosis

Pathogenic:1

Oct 28, 2015

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R248C variant (also known as c.742C>T and p.R236C) is located in coding exon 7 of the SFTPB gene. This alteration results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was described in an affected infant with the common c.397delCinsGAA mutation (referred to as 121ins2) on the other chromosome. This patient presented with significantly reduced levels of mature surfactant protein B (Ballard PL et al. Pediatrics. 1995;96(6):1046-1052). This amino acid position is not well conserved in available vertebrate species. This variant was previously reported in the SNPDatabase as rs137853202. Based on data from the NHLBI Exome Sequencing Project (ESP), the T-allele has an overall frequency of approximately 0.02% (2/12,898), having been observed in 0.05% (2/4,354) of African American alleles, and was not observed in 8,544 of European American alleles studied. This variant was not reported in population-based cohorts in the 1000 Genomes Project. This variant is predicted to be possibly damaging by PolyPhen and deleterious by SIFT in silico analyses. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Uncertain:1

Jan 15, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7491219, 15819986, 28888561, 36445537) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;D;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.79

.;T;T

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.0

L;L;.

PhyloP100

4.2

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.5

.;.;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.020

.;.;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.77

MVP

0.93

MPC

0.35

ClinPred

0.25

GERP RS

4.4

PromoterAI

0.043

Neutral

(source)

Varity_R

0.21

gMVP

0.43

Mutation Taster

=83/17

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over