rs1130866

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000542.5(SFTPB):c.392C>T(p.Thr131Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,612,412 control chromosomes in the GnomAD database, including 220,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 25598 hom., cov: 30)

Exomes 𝑓: 0.51 ( 194575 hom. )

Consequence

SFTPB
NM_000542.5 missense, splice_region

Scores

Splicing: ADA: 0.0007824

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.98

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1985506E-6).

BP6

Variant 2-85666618-G-A is Benign according to our data. Variant chr2-85666618-G-A is described in ClinVar as [Benign]. Clinvar id is 165204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-85666618-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPB	NM_000542.5 linkuse as main transcript	c.392C>T	p.Thr131Ile	missense_variant, splice_region_variant	4/11	ENST00000519937.7	NP_000533.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPB	ENST00000519937.7 linkuse as main transcript	c.392C>T	p.Thr131Ile	missense_variant, splice_region_variant	4/11	1	NM_000542.5	ENSP00000428719	P1

Frequencies

GnomAD3 genomes

AF:

0.567

AC:

85877

AN:

151492

Hom.:

25579

Cov.:

show subpopulations

Gnomad AFR

AF:

0.745

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.455

Gnomad ASJ

AF:

0.530

Gnomad EAS

AF:

0.264

Gnomad SAS

AF:

0.441

Gnomad FIN

AF:

0.516

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.526

Gnomad OTH

AF:

0.544

GnomAD3 exomes

AF:

0.495

AC:

124356

AN:

251164

Hom.:

32253

AF XY:

0.495

AC XY:

67144

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.754

Gnomad AMR exome

AF:

0.405

Gnomad ASJ exome

AF:

0.521

Gnomad EAS exome

AF:

0.264

Gnomad SAS exome

AF:

0.450

Gnomad FIN exome

AF:

0.529

Gnomad NFE exome

AF:

0.526

Gnomad OTH exome

AF:

0.501

GnomAD4 exome

AF:

0.512

AC:

747528

AN:

1460802

Hom.:

194575

Cov.:

AF XY:

0.511

AC XY:

371138

AN XY:

726722

show subpopulations

Gnomad4 AFR exome

AF:

0.759

Gnomad4 AMR exome

AF:

0.414

Gnomad4 ASJ exome

AF:

0.519

Gnomad4 EAS exome

AF:

0.266

Gnomad4 SAS exome

AF:

0.457

Gnomad4 FIN exome

AF:

0.528

Gnomad4 NFE exome

AF:

0.520

Gnomad4 OTH exome

AF:

0.515

GnomAD4 genome

AF:

0.567

AC:

85936

AN:

151610

Hom.:

25598

Cov.:

AF XY:

0.562

AC XY:

41612

AN XY:

74088

show subpopulations

Gnomad4 AFR

AF:

0.745

Gnomad4 AMR

AF:

0.454

Gnomad4 ASJ

AF:

0.530

Gnomad4 EAS

AF:

0.264

Gnomad4 SAS

AF:

0.440

Gnomad4 FIN

AF:

0.516

Gnomad4 NFE

AF:

0.526

Gnomad4 OTH

AF:

0.536

Alfa

AF:

0.518

Hom.:

52882

Bravo

AF:

0.568

TwinsUK

AF:

0.512

AC:

1899

ALSPAC

AF:

0.525

AC:

2022

ESP6500AA

AF:

0.743

AC:

3275

ESP6500EA

AF:

0.525

AC:

4514

ExAC

AF:

0.503

AC:

61107

Asia WGS

AF:

0.411

AC:

1430

AN:

3478

EpiCase

AF:

0.522

EpiControl

AF:

0.528

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2016	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2018	This variant is associated with the following publications: (PMID: 23330012, 11076040, 26620227) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Surfactant metabolism dysfunction, pulmonary, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary pulmonary alveolar proteinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.11

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.18

.;T;T

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.6

N;N;.

MutationTaster

Benign

0.15

P;P;P

PrimateAI

Uncertain

0.52

PROVEAN

Benign

2.7

.;.;N

REVEL

Benign

0.15

Sift

Benign

1.0

.;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.059

MPC

0.28

ClinPred

0.0018

GERP RS

3.3

Varity_R

0.036

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00078

dbscSNV1_RF

Benign

0.25

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

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