rs1059047

Variant names:

• chr10-79611881-T-C
• rs1059047
• NM_005411.5:c.56T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005411.5(SFTPA1):​c.56T>C​(p.Val19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0867 in 1,431,716 control chromosomes in the GnomAD database, including 6,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (578 hom., cov: 32)
  • Exomes 𝑓: 0.087 (6006 hom.)
• Consequence: SFTPA1 NM_005411.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.457
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• interstitial lung disease 1

  Inheritance: AD, SD Classification: STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017886162).
• BP6: Variant 10-79611881-T-C is Benign according to our data. Variant chr10-79611881-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA1	NM_005411.5	MANE Select	c.56T>C	p.Val19Ala	missense	Exon 3 of 6	NP_005402.3
	SFTPA1	NM_001093770.3		c.101T>C	p.Val34Ala	missense	Exon 3 of 6	NP_001087239.2	Q8IWL2-2
	SFTPA1	NM_001164644.2		c.56T>C	p.Val19Ala	missense	Exon 3 of 6	NP_001158116.1	Q8IWL2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA1	ENST00000398636.8	TSL:1 MANE Select	c.56T>C	p.Val19Ala	missense	Exon 3 of 6	ENSP00000381633.3	Q8IWL2-1
	SFTPA1	ENST00000419470.6	TSL:1	c.101T>C	p.Val34Ala	missense	Exon 3 of 6	ENSP00000397082.2	Q8IWL2-2
	SFTPA1	ENST00000428376.6	TSL:1	c.56T>C	p.Val19Ala	missense	Exon 2 of 5	ENSP00000411102.2	Q8IWL2-1

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 10823 AN: 122556 Hom.: 571 Cov.: 32

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.0169

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.0949

Gnomad EAS AF: 0.0249

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.0777

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0941

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0779 AC: 18458 AN: 237012 AF XY: 0.0782

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.0487

Gnomad EAS exome AF: 0.0134

Gnomad FIN exome AF: 0.0434

Gnomad NFE exome AF: 0.0530

Gnomad OTH exome AF: 0.0790

GnomAD4 exome AF: 0.0866 AC: 113321 AN: 1309066 Hom.: 6006 Cov.: 121 AF XY: 0.0892 AC XY: 58301 AN XY: 653952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0192 AC: 617 AN: 32168

American (AMR) AF: 0.243 AC: 10128 AN: 41692

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 1928 AN: 24774

East Asian (EAS) AF: 0.0271 AC: 1001 AN: 36934

South Asian (SAS) AF: 0.191 AC: 15868 AN: 83222

European-Finnish (FIN) AF: 0.0555 AC: 2766 AN: 49830

Middle Eastern (MID) AF: 0.110 AC: 601 AN: 5476

European-Non Finnish (NFE) AF: 0.0773 AC: 75754 AN: 980518

Other (OTH) AF: 0.0855 AC: 4658 AN: 54452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0884 AC: 10846 AN: 122650 Hom.: 578 Cov.: 32 AF XY: 0.0932 AC XY: 5576 AN XY: 59842

African (AFR) AF: 0.0279 AC: 995 AN: 35680

American (AMR) AF: 0.215 AC: 2678 AN: 12466

Ashkenazi Jewish (ASJ) AF: 0.0949 AC: 285 AN: 3004

East Asian (EAS) AF: 0.0249 AC: 108 AN: 4330

South Asian (SAS) AF: 0.244 AC: 982 AN: 4028

European-Finnish (FIN) AF: 0.0777 AC: 576 AN: 7416

Middle Eastern (MID) AF: 0.0859 AC: 22 AN: 256

European-Non Finnish (NFE) AF: 0.0941 AC: 4993 AN: 53080

Other (OTH) AF: 0.113 AC: 196 AN: 1738

Alfa AF: 0.0832 Hom.: 85

ExAC AF: 0.0923 AC: 11209

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	See cases (1)
-	-	1	SFTPA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.034
DANN	Benign	0.23
DEOGEN2	Benign	0.042	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.049	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.46
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.017
ClinPred		0.0064	T
GERP RS		-5.3
Varity_R		0.018
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1059047; hg19: chr10-81371637; COSMIC: COSV64866768;