10-79557300-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_001098668.4(SFTPA2):c.656G>A(p.Arg219Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SFTPA2
NM_001098668.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.340

Publications

4 publications found

Variant links:

Genes affected

SFTPA2 (HGNC:10799): (surfactant protein A2) This gene is one of several genes encoding pulmonary-surfactant associated proteins (SFTPA) located on chromosome 10. Mutations in this gene and a highly similar gene located nearby, which affect the highly conserved carbohydrate recognition domain, are associated with idiopathic pulmonary fibrosis. The current version of the assembly displays only a single centromeric SFTPA gene pair rather than the two gene pairs shown in the previous assembly which were thought to have resulted from a duplication. [provided by RefSeq, Sep 2009]

SFTPA2 Gene-Disease associations (from GenCC):

interstitial lung disease 2
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
interstitial lung disease 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
idiopathic pulmonary fibrosis
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp

SFTPA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM1

In a domain C-type lectin (size 116) in uniprot entity SFPA2_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001098668.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0576787).

BS2

High AC in GnomAdExome4 at 18 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098668.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SFTPA2	NM_001098668.4	MANE Select	c.656G>A	p.Arg219Gln	missense	Exon 6 of 6	NP_001092138.1	Q8IWL1
SFTPA2	NM_001320814.1		c.686G>A	p.Arg229Gln	missense	Exon 5 of 5	NP_001307743.1
SFTPA2	NM_001320813.2		c.656G>A	p.Arg219Gln	missense	Exon 6 of 6	NP_001307742.1	Q8IWL1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SFTPA2	ENST00000372325.7	TSL:1 MANE Select	c.656G>A	p.Arg219Gln	missense	Exon 6 of 6	ENSP00000361400.2	Q8IWL1
SFTPA2	ENST00000372327.9	TSL:1	c.656G>A	p.Arg219Gln	missense	Exon 5 of 5	ENSP00000361402.5	Q8IWL1
SFTPA2	ENST00000959071.1		c.785G>A	p.Arg262Gln	missense	Exon 6 of 6	ENSP00000629130.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152168

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251470

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2086

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.75

CADD

Benign

1.5

(source)

DANN

Benign

0.82

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0022

M_CAP

Benign

0.0018

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.96

PhyloP100

-0.34

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.060

REVEL

Benign

0.0090

Sift

Benign

0.28

Sift4G

Benign

0.42

Vest4

0.091

MutPred

0.35

Gain of methylation at K221 (P = 0.126)

MVP

0.11

MPC

1.2

ClinPred

0.033

GERP RS

-0.91

gMVP

0.25

Mutation Taster

=97/3

polymorphism

(source)

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

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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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over