NM_000542.5:c.526C>T

Variant names:

• chr2-85665662-G-A
• rs3024801
• NM_000542.5:c.526C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000542.5(SFTPB):​c.526C>T​(p.Leu176Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,614,180 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: SFTPB NM_000542.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0490

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003846556).
• BP6: Variant 2-85665662-G-A is Benign according to our data. Variant chr2-85665662-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 596954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00234 (357/152344) while in subpopulation AFR AF= 0.00786 (327/41580). AF 95% confidence interval is 0.00716. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPB	NM_000542.5	c.526C>T	p.Leu176Phe	missense_variant	Exon 5 of 11	ENST00000519937.7	NP_000533.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPB	ENST00000519937.7	c.526C>T	p.Leu176Phe	missense_variant	Exon 5 of 11	1	NM_000542.5	ENSP00000428719.2
SFTPB	ENST00000393822.7	c.526C>T	p.Leu176Phe	missense_variant	Exon 6 of 12	1		ENSP00000377409.4
SFTPB	ENST00000409383.6	c.526C>T	p.Leu176Phe	missense_variant	Exon 6 of 12	1		ENSP00000386346.2
SFTPB	ENST00000428225.5	c.514C>T	p.Leu172Phe	missense_variant	Exon 5 of 11	2		ENSP00000415347.1

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 356 AN: 152226 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00786

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000705 AC: 177 AN: 251166 Hom.: 1 AF XY: 0.000493 AC XY: 67 AN XY: 135816

Gnomad AFR exome AF: 0.00779

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000305 AC: 446 AN: 1461836 Hom.: 2 Cov.: 32 AF XY: 0.000282 AC XY: 205 AN XY: 727214

Gnomad4 AFR exome AF: 0.00750

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152344 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74502

Gnomad4 AFR AF: 0.00786

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000557 Hom.: 0

Bravo AF: 0.00258

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000923 AC: 112

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SFTPB: BP4, BS2 -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 07, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SFTPB-related disorder Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary pulmonary alveolar proteinosis Benign:1

Nov 25, 2019

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. -

Surfactant metabolism dysfunction, pulmonary, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T
Eigen	Benign	0.024
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.75	.;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0038	T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	.;N;N
REVEL	Benign	0.19
Sift	Benign	0.038	.;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.30
MVP		0.85
MPC		0.90
ClinPred		0.031	T
GERP RS		4.0
Varity_R		0.11
gMVP		0.37

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

Other links and lift over

dbSNP: rs3024801; hg19: chr2-85892785;