rs1130866

Variant names:

• chr2-85666618-G-A
• rs1130866
• NM_000542.5:c.392C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-85666618-G-A
• chr2-85666618-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 17/23 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
• Publications: 120 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: Benign. The variant received -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 VariationId is 165204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SFTPB	NM_000542.5	c.392C>T	p.Thr131Ile	missense_variant, splice_region_variant	Exon 4 of 11	ENST00000519937.7	NP_000533.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPB	ENST00000519937.7	c.392C>T	p.Thr131Ile	missense_variant, splice_region_variant	Exon 4 of 11	1	NM_000542.5	ENSP00000428719.2

Frequencies

GnomAD3 genomes AF: 0.567 AC: 85877 AN: 151492 Hom.: 25579 Cov.: 30

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

GnomAD2 exomes AF: 0.495 AC: 124356 AN: 251164 AF XY: 0.495

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 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.: 48 AF XY: 0.511 AC XY: 371138 AN XY: 726722

African (AFR) AF: 0.759 AC: 25383 AN: 33440

American (AMR) AF: 0.414 AC: 18498 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 13549 AN: 26110

East Asian (EAS) AF: 0.266 AC: 10540 AN: 39628

South Asian (SAS) AF: 0.457 AC: 39437 AN: 86236

European-Finnish (FIN) AF: 0.528 AC: 28134 AN: 53290

Middle Eastern (MID) AF: 0.554 AC: 3192 AN: 5762

European-Non Finnish (NFE) AF: 0.520 AC: 577715 AN: 1111300

Other (OTH) AF: 0.515 AC: 31080 AN: 60350

GnomAD4 genome AF: 0.567 AC: 85936 AN: 151610 Hom.: 25598 Cov.: 30 AF XY: 0.562 AC XY: 41612 AN XY: 74088

African (AFR) AF: 0.745 AC: 30768 AN: 41302

American (AMR) AF: 0.454 AC: 6917 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.530 AC: 1839 AN: 3468

East Asian (EAS) AF: 0.264 AC: 1356 AN: 5134

South Asian (SAS) AF: 0.440 AC: 2114 AN: 4810

European-Finnish (FIN) AF: 0.516 AC: 5442 AN: 10554

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.526 AC: 35702 AN: 67812

Other (OTH) AF: 0.536 AC: 1127 AN: 2104

Alfa AF: 0.527 Hom.: 103014

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

Submissions by phenotype

not specified Benign:3

Oct 05, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23330012, 11076040, 26620227) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Surfactant metabolism dysfunction, pulmonary, 1 Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
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	N
LIST_S2	Benign	0.18	.;T;T
MetaRNN	Benign	0.0000012	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.6	N;N;.
PhyloP100		2.0
PrimateAI	Uncertain	0.52	T
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	T
GERP RS		3.3
Varity_R		0.036
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1130866; hg19: chr2-85893741; COSMIC: COSV60892835; COSMIC: COSV60892835;