rs45557339

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS1_Supporting

The NM_000542.5(SFTPB):c.352G>A(p.Asp118Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 1 hom. )

Consequence

SFTPB
NM_000542.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -2.90

Publications

3 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

SFTPB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000542.5

BP4

Computational evidence support a benign effect (MetaRNN=0.017415464).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000184 (28/152102) while in subpopulation EAS AF = 0.00136 (7/5164). AF 95% confidence interval is 0.000635. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000542.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SFTPB	NM_000542.5	MANE Select	c.352G>A	p.Asp118Asn	missense	Exon 4 of 11	NP_000533.4
SFTPB	NM_198843.3		c.352G>A	p.Asp118Asn	missense	Exon 5 of 12	NP_942140.3	P07988
SFTPB	NM_001367281.1		c.352G>A	p.Asp118Asn	missense	Exon 4 of 9	NP_001354210.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SFTPB	ENST00000519937.7	TSL:1 MANE Select	c.352G>A	p.Asp118Asn	missense	Exon 4 of 11	ENSP00000428719.2	P07988
SFTPB	ENST00000393822.7	TSL:1	c.352G>A	p.Asp118Asn	missense	Exon 5 of 12	ENSP00000377409.4	P07988
SFTPB	ENST00000409383.7	TSL:1	c.352G>A	p.Asp118Asn	missense	Exon 5 of 12	ENSP00000386346.2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000211

AC:

AN:

251384

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000992

AC:

145

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26124

East Asian (EAS)

AF:

0.000554

AC:

AN:

39698

South Asian (SAS)

AF:

0.000104

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000962

AC:

107

AN:

1111882

Other (OTH)

AF:

0.0000828

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000184

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41480

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00136

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

67958

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000205

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Surfactant metabolism dysfunction, pulmonary, 1 (2)

Hereditary pulmonary alveolar proteinosis (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.26

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.11

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.61

M_CAP

Benign

0.016

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-2.9

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.66

REVEL

Benign

0.064

Sift

Benign

0.34

Sift4G

Benign

0.12

Polyphen

0.21

Vest4

0.14

MVP

0.61

MPC

0.25

ClinPred

0.020

GERP RS

-6.2

Varity_R

0.077

gMVP

0.21

Mutation Taster

=98/2

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over