rs121917737

Variant names:

• chr10-79557264-C-A
• rs121917737
• NM_001098668.4:c.692G>T
• SFTPA2 p.Gly231Val

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001098668.4(SFTPA2):​c.692G>T​(p.Gly231Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Pathogenic/Likely risk allele no assertion criteria provided P:2
• Conservation: PhyloP100: 3.94
• Publications: 19 publications found

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, STRONG Submitted by: ClinGen, PanelApp Australia
• interstitial lung disease 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• idiopathic pulmonary fibrosis

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a disulfide_bond (size 91) in uniprot entity SFPA2_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_001098668.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-79557264-C-A is Pathogenic according to our data. Variant chr10-79557264-C-A is described in ClinVar as Pathogenic/Likely_risk_allele. ClinVar VariationId is 13199.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA2	NM_001098668.4	MANE Select	c.692G>T	p.Gly231Val	missense	Exon 6 of 6	NP_001092138.1	Q8IWL1
	SFTPA2	NM_001320814.1		c.722G>T	p.Gly241Val	missense	Exon 5 of 5	NP_001307743.1
	SFTPA2	NM_001320813.2		c.692G>T	p.Gly231Val	missense	Exon 6 of 6	NP_001307742.1	Q8IWL1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA2	ENST00000372325.7	TSL:1 MANE Select	c.692G>T	p.Gly231Val	missense	Exon 6 of 6	ENSP00000361400.2	Q8IWL1
	SFTPA2	ENST00000372327.9	TSL:1	c.692G>T	p.Gly231Val	missense	Exon 5 of 5	ENSP00000361402.5	Q8IWL1
	SFTPA2	ENST00000959071.1		c.821G>T	p.Gly274Val	missense	Exon 6 of 6	ENSP00000629130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely risk allele

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Interstitial lung disease 2 (1)
-	-	-	Pulmonary fibrosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.35	D
PhyloP100		3.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
gMVP		0.91
Mutation Taster		=8/92	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121917737;

hg19: chr10-81317020;