10-79557289-G-T

Variant names:

• chr10-79557289-G-T
• rs1965708
• NM_001098668.4:c.667C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001098668.4(SFTPA2):​c.667C>A​(p.Gln223Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,734 control chromosomes in the GnomAD database, including 38,163 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5277 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32886 hom.)
• Consequence: SFTPA2 NM_001098668.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.945
• Publications: 65 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: PanelApp Australia, ClinGen
• 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: Benign. The variant received -18 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=0.0025300682).
• BP6: Variant 10-79557289-G-T is Benign according to our data. Variant chr10-79557289-G-T is described in ClinVar as Benign. ClinVar VariationId is 227071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

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.667C>A	p.Gln223Lys	missense	Exon 6 of 6	NP_001092138.1	Q8IWL1
	SFTPA2	NM_001320814.1		c.697C>A	p.Gln233Lys	missense	Exon 5 of 5	NP_001307743.1
	SFTPA2	NM_001320813.2		c.667C>A	p.Gln223Lys	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.667C>A	p.Gln223Lys	missense	Exon 6 of 6	ENSP00000361400.2	Q8IWL1
	SFTPA2	ENST00000372327.9	TSL:1	c.667C>A	p.Gln223Lys	missense	Exon 5 of 5	ENSP00000361402.5	Q8IWL1
	SFTPA2	ENST00000959071.1		c.796C>A	p.Gln266Lys	missense	Exon 6 of 6	ENSP00000629130.1

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37959 AN: 151766 Hom.: 5265 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.217 AC: 54596 AN: 251408 AF XY: 0.223

Gnomad AFR exome AF: 0.373

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.307

Gnomad EAS exome AF: 0.192

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.201

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.207 AC: 301937 AN: 1461850 Hom.: 32886 Cov.: 34 AF XY: 0.210 AC XY: 152941 AN XY: 727230

African (AFR) AF: 0.385 AC: 12871 AN: 33474

American (AMR) AF: 0.137 AC: 6125 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 8075 AN: 26136

East Asian (EAS) AF: 0.196 AC: 7763 AN: 39700

South Asian (SAS) AF: 0.289 AC: 24887 AN: 86250

European-Finnish (FIN) AF: 0.215 AC: 11480 AN: 53416

Middle Eastern (MID) AF: 0.320 AC: 1843 AN: 5768

European-Non Finnish (NFE) AF: 0.194 AC: 215836 AN: 1111994

Other (OTH) AF: 0.216 AC: 13057 AN: 60396

GnomAD4 genome AF: 0.250 AC: 38017 AN: 151884 Hom.: 5277 Cov.: 32 AF XY: 0.249 AC XY: 18518 AN XY: 74222

African (AFR) AF: 0.370 AC: 15324 AN: 41362

American (AMR) AF: 0.165 AC: 2524 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1059 AN: 3472

East Asian (EAS) AF: 0.188 AC: 975 AN: 5178

South Asian (SAS) AF: 0.269 AC: 1298 AN: 4818

European-Finnish (FIN) AF: 0.206 AC: 2174 AN: 10538

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13937 AN: 67932

Other (OTH) AF: 0.244 AC: 515 AN: 2110

Alfa AF: 0.229 Hom.: 2278

Bravo AF: 0.248

TwinsUK AF: 0.190 AC: 705

ALSPAC AF: 0.188 AC: 724

ESP6500AA AF: 0.358 AC: 1576

ESP6500EA AF: 0.200 AC: 1718

ExAC AF: 0.222 AC: 26906

EpiCase AF: 0.215

EpiControl AF: 0.212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Interstitial lung disease 2 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.20
DANN	Benign	0.30
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0024	N
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.94
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.014
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.047
MPC		1.3
ClinPred		0.0031	T
GERP RS		-3.2
gMVP		0.50
Mutation Taster		=95/5	polymorphism (auto)

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: rs1965708; hg19: chr10-81317045; COSMIC: COSV64882436; COSMIC: COSV64882436;