rs137853202

Positions:

chr2-85663814-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The ENST00000519937.7(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
ENST00000519937.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.19

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 id is 13204.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPB	NM_000542.5 linkuse as main transcript	c.706C>T	p.Arg236Cys	missense_variant	7/11	ENST00000519937.7	NP_000533.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SFTPB	ENST00000519937.7 linkuse as main transcript	c.706C>T	p.Arg236Cys	missense_variant	7/11	1	NM_000542.5	ENSP00000428719	P1
SFTPB	ENST00000393822.7 linkuse as main transcript	c.706C>T	p.Arg236Cys	missense_variant	8/12	1		ENSP00000377409	P1
SFTPB	ENST00000409383.6 linkuse as main transcript	c.706C>T	p.Arg236Cys	missense_variant	8/12	1		ENSP00000386346	P1
SFTPB	ENST00000428225.5 linkuse as main transcript	c.697C>T	p.Arg233Cys	missense_variant	7/11	2		ENSP00000415347

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

GnomAD3 exomes

AF:

0.0000287

AC:

AN:

209002

Hom.:

AF XY:

0.00000872

AC XY:

AN XY:

114714

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.000482

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000262

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.000138

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

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

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 04, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1995	- -

Hereditary pulmonary alveolar proteinosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 28, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 09, 2021

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) -

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

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;.

MutationTaster

Benign

0.96

A;A;A

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

Varity_R

0.21

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over