rs139806726

Positions:

chr10-79613943-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_005411.5(SFTPA1):c.577C>T(p.Pro193Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SFTPA1
NM_005411.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.732

Variant links:

Genes affected

SFTPA1 (HGNC:10798): (surfactant protein A1) This gene encodes a lung surfactant protein that is a member of a subfamily of C-type lectins called collectins. The encoded protein binds specific carbohydrate moieties found on lipids and on the surface of microorganisms. This protein plays an essential role in surfactant homeostasis and in the defense against respiratory pathogens. Mutations in this gene are associated with idiopathic pulmonary fibrosis. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

SFTPA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1

In a disulfide_bond (size 91) in uniprot entity SFTA1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005411.5

BP4

Computational evidence support a benign effect (MetaRNN=0.056151748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPA1	NM_005411.5 linkuse as main transcript	c.577C>T	p.Pro193Ser	missense_variant	6/6	ENST00000398636.8	NP_005402.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPA1	ENST00000398636.8 linkuse as main transcript	c.577C>T	p.Pro193Ser	missense_variant	6/6	1	NM_005411.5	ENSP00000381633	P1	Q8IWL2-1
SFTPA1	ENST00000419470.6 linkuse as main transcript	c.622C>T	p.Pro208Ser	missense_variant	6/6	1		ENSP00000397082		Q8IWL2-2
SFTPA1	ENST00000428376.6 linkuse as main transcript	c.577C>T	p.Pro193Ser	missense_variant	5/5	1		ENSP00000411102	P1	Q8IWL2-1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152244

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251422

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000237

AC:

346

AN:

1461770

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

175

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 18, 2013

Variant classified as Uncertain Significance - Favor Benign. The Pro208Ser varia nt in SFTPA1 has not been previously identified in individuals with idiopathic p ulmonary fibrosis, but has been identified in 0.05% (4/8592) European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs139806726). Proline (Pro) at position 208 is poorly conserved in ev olution and at least 2 mammalian species (elephant and rock hyrax) carry the var iant amino acid (serine, Ser), raising the possibility that this change may be t olerated. Additional computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the pro tein, though this information is not predictive enough to rule out pathogenicity . In summary, the lack of evolutionary conservation suggests that this variant m ay be more likely benign, but additional information is needed to fully assess i ts clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.3

DANN

Benign

0.29

DEOGEN2

Benign

0.027

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0095

LIST_S2

Benign

0.51

.;T;T

M_CAP

Benign

0.0022

MetaRNN

Benign

0.056

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.30

N;N;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.0060

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.063

B;B;.

Vest4

0.11

MVP

0.14

MPC

0.96

ClinPred

0.049

GERP RS

-0.45

Varity_R

0.040

gMVP

0.39

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