rs777910370

Variant names:

• chr10-79557300-C-A
• rs777910370
• NM_001098668.4:c.656G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-79557300-C-A
• chr10-79557300-C-G
• chr10-79557300-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001098668.4(SFTPA2):​c.656G>T​(p.Arg219Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: not found (cov: 31)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.340
• Publications: 4 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 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10345444).

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.656G>T	p.Arg219Leu	missense	Exon 6 of 6	NP_001092138.1	Q8IWL1
	SFTPA2	NM_001320814.1		c.686G>T	p.Arg229Leu	missense	Exon 5 of 5	NP_001307743.1
	SFTPA2	NM_001320813.2		c.656G>T	p.Arg219Leu	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.656G>T	p.Arg219Leu	missense	Exon 6 of 6	ENSP00000361400.2	Q8IWL1
	SFTPA2	ENST00000372327.9	TSL:1	c.656G>T	p.Arg219Leu	missense	Exon 5 of 5	ENSP00000361402.5	Q8IWL1
	SFTPA2	ENST00000959071.1		c.785G>T	p.Arg262Leu	missense	Exon 6 of 6	ENSP00000629130.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.5
DANN	Benign	0.85
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0078	N
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.34
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.013
Sift	Benign	0.071	T
Sift4G	Uncertain	0.053	T
Vest4		0.15
MutPred		0.36		Loss of disorder (P = 0.0496)
MVP		0.13
MPC		1.3
ClinPred		0.043	T
GERP RS		-0.91
gMVP		0.44
Mutation Taster		=91/9	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: rs777910370; hg19: chr10-81317056;