rs3024801

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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
• Publications: 9 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=0.003846556).
• BP6: Variant 2-85665662-G-A is Benign according to our data. Variant chr2-85665662-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPB	NM_000542.5	MANE Select	c.526C>T	p.Leu176Phe	missense	Exon 5 of 11	NP_000533.4
	SFTPB	NM_198843.3		c.526C>T	p.Leu176Phe	missense	Exon 6 of 12	NP_942140.3
	SFTPB	NM_001367281.1		c.526C>T	p.Leu176Phe	missense	Exon 5 of 9	NP_001354210.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPB	ENST00000519937.7	TSL:1 MANE Select	c.526C>T	p.Leu176Phe	missense	Exon 5 of 11	ENSP00000428719.2
	SFTPB	ENST00000393822.7	TSL:1	c.526C>T	p.Leu176Phe	missense	Exon 6 of 12	ENSP00000377409.4
	SFTPB	ENST00000409383.7	TSL:1	c.526C>T	p.Leu176Phe	missense	Exon 6 of 12	ENSP00000386346.2

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

GnomAD2 exomes AF: 0.000705 AC: 177 AN: 251166 AF XY: 0.000493

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 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

African (AFR) AF: 0.00750 AC: 251 AN: 33478

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53412

Middle Eastern (MID) AF: 0.00314 AC: 18 AN: 5732

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1112008

Other (OTH) AF: 0.000712 AC: 43 AN: 60392

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

African (AFR) AF: 0.00786 AC: 327 AN: 41580

American (AMR) AF: 0.000653 AC: 10 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000877 Hom.: 1

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	not specified (1)
-	-	1	SFTPB-related disorder (1)
-	-	1	Surfactant metabolism dysfunction, pulmonary, 1 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.024
Eigen_PC	Benign	-0.071
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.049
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.19
Sift	Benign	0.038	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs3024801; hg19: chr2-85892785;