Genetic Variant NM_005411.5:c.655C>T (chr10-79614021-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_005411.5(SFTPA1):c.655C>T(p.Arg219Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,614,084 control chromosomes in the GnomAD database, including 7,308 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.092 ( 750 hom., cov: 32)

Exomes 𝑓: 0.089 ( 6558 hom. )

Consequence

SFTPA1
NM_005411.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: -0.198

Publications

46 publications found

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 was made for transcript

Our verdict: Benign. The variant received -18 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, 7 uncertain in NM_005411.5

BP4

Computational evidence support a benign effect (MetaRNN=0.00728637).

BP6

Variant 10-79614021-C-T is Benign according to our data. Variant chr10-79614021-C-T is described in ClinVar as Benign. ClinVar VariationId is 13206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005411.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SFTPA1	NM_005411.5	MANE Select	c.655C>T	p.Arg219Trp	missense	Exon 6 of 6	NP_005402.3
SFTPA1	NM_001093770.3		c.700C>T	p.Arg234Trp	missense	Exon 6 of 6	NP_001087239.2
SFTPA1	NM_001164644.2		c.655C>T	p.Arg219Trp	missense	Exon 6 of 6	NP_001158116.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SFTPA1	ENST00000398636.8	TSL:1 MANE Select	c.655C>T	p.Arg219Trp	missense	Exon 6 of 6	ENSP00000381633.3
SFTPA1	ENST00000419470.6	TSL:1	c.700C>T	p.Arg234Trp	missense	Exon 6 of 6	ENSP00000397082.2
SFTPA1	ENST00000428376.6	TSL:1	c.655C>T	p.Arg219Trp	missense	Exon 5 of 5	ENSP00000411102.2

Frequencies

GnomAD3 genomes

AF:

0.0921

AC:

14015

AN:

152094

Hom.:

749

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0700

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.147

Gnomad EAS

AF:

0.240

Gnomad SAS

AF:

0.0739

Gnomad FIN

AF:

0.0986

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.0874

Gnomad OTH

AF:

0.114

GnomAD2 exomes

AF:

0.102

AC:

25641

AN:

251448

AF XY:

0.0999

show subpopulations

Gnomad AFR exome

AF:

0.0740

Gnomad AMR exome

AF:

0.0916

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.256

Gnomad FIN exome

AF:

0.104

Gnomad NFE exome

AF:

0.0899

Gnomad OTH exome

AF:

0.106

GnomAD4 exome

AF:

0.0887

AC:

129695

AN:

1461870

Hom.:

6558

Cov.:

AF XY:

0.0882

AC XY:

64130

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0720

AC:

2412

AN:

33480

American (AMR)

AF:

0.0908

AC:

4060

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3751

AN:

26136

East Asian (EAS)

AF:

0.225

AC:

8914

AN:

39700

South Asian (SAS)

AF:

0.0644

AC:

5556

AN:

86258

European-Finnish (FIN)

AF:

0.108

AC:

5758

AN:

53418

Middle Eastern (MID)

AF:

0.114

AC:

660

AN:

5768

European-Non Finnish (NFE)

AF:

0.0831

AC:

92420

AN:

1111990

Other (OTH)

AF:

0.102

AC:

6164

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

10020

20039

30059

40078

50098

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3432

6864

10296

13728

17160

<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:

0.0921

AC:

14026

AN:

152214

Hom.:

750

Cov.:

AF XY:

0.0941

AC XY:

7003

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0700

AC:

2906

AN:

41522

American (AMR)

AF:

0.106

AC:

1622

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

510

AN:

3470

East Asian (EAS)

AF:

0.241

AC:

1246

AN:

5178

South Asian (SAS)

AF:

0.0742

AC:

358

AN:

4824

European-Finnish (FIN)

AF:

0.0986

AC:

1046

AN:

10606

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0874

AC:

5944

AN:

68002

Other (OTH)

AF:

0.117

AC:

246

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

643

1286

1928

2571

3214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

304

456

608

760

<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:

0.0866

Hom.:

1173

Bravo

AF:

0.0930

TwinsUK

AF:

0.0828

AC:

307

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.0801

AC:

353

ESP6500EA

AF:

0.0868

AC:

746

ExAC

AF:

0.100

AC:

12177

Asia WGS

AF:

0.156

AC:

541

AN:

3478

EpiCase

AF:

0.0909

EpiControl

AF:

0.0984

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Pulmonary fibrosis, idiopathic, susceptibility to (1)

SFTPA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.1

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.16

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.82

PhyloP100

-0.20

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.061

Sift

Benign

0.060

Sift4G

Uncertain

0.048

Polyphen

0.026

Vest4

0.10

MPC

0.97

ClinPred

0.010

GERP RS

1.9

Varity_R

0.13

gMVP

0.64

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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