2-85666658-C-T

Position:

chr2-85666658-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_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. 16/21 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:3

Conservation

PhyloP100: -2.90

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:

SFTPB (HGNC:):

SFTPB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPB	NM_000542.5 linkuse as main transcript	c.352G>A	p.Asp118Asn	missense_variant	4/11	ENST00000519937.7	NP_000533.4	P07988D6W5L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPB	ENST00000519937.7 linkuse as main transcript	c.352G>A	p.Asp118Asn	missense_variant	4/11	1	NM_000542.5	ENSP00000428719.2		P07988

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

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251384

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135868

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 SAS exome

AF:

0.0000980

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000554

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000962

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000184

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

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

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 130 of the SFTPB protein (p.Asp130Asn). This variant is present in population databases (rs45557339, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SFTPB-related conditions. ClinVar contains an entry for this variant (Variation ID: 619287). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SFTPB protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary pulmonary alveolar proteinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The c.388G>A (p.D130N) alteration is located in exon 5 (coding exon 4) of the SFTPB gene. This alteration results from a G to A substitution at nucleotide position 388, causing the aspartic acid (D) at amino acid position 130 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Surfactant metabolism dysfunction, pulmonary, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

Feb 08, 2019

SFTPB c.352G>A has not been reported in ClinVar nor the literature, to our knowledge. This variant (rs45557339) is rare in large population datasets (gnomAD: 68/282654 alleles; 0.02406%, no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the aspartic acid residue at this position is not evolutionarily conserved across species assessed. Due to insufficient evidence that this variant is deleterious, the clinical significance of c.352G>A is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.26

DANN

Benign

0.90

DEOGEN2

Benign

0.11

T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.61

.;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

N;N;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.66

.;.;N

REVEL

Benign

0.064

Sift

Benign

0.34

.;.;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.21

B;B;B

Vest4

0.14

MVP

0.61

MPC

0.25

ClinPred

0.020

GERP RS

-6.2

Varity_R

0.077

gMVP

0.21

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

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