rs1059047

chr10-79611881-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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:5
• Conservation: PhyloP100: -0.457

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA1	NM_005411.5	c.56T>C	p.Val19Ala	missense_variant	3/6	ENST00000398636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA1	ENST00000398636.8	c.56T>C	p.Val19Ala	missense_variant	3/6	1	NM_005411.5	P1

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

GnomAD3 exomes AF: 0.0779 AC: 18458 AN: 237012 Hom.: 1906 AF XY: 0.0782 AC XY: 10002 AN XY: 127874

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 SAS exome AF: 0.149

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

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.0778

Gnomad4 EAS exome AF: 0.0271

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.0555

Gnomad4 NFE exome AF: 0.0773

Gnomad4 OTH exome AF: 0.0855

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

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.0949

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.0777

Gnomad4 NFE AF: 0.0941

Gnomad4 OTH AF: 0.113

Alfa AF: 0.0832 Hom.: 85

ExAC AF: 0.0923 AC: 11209

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2015

This is a homologous region and while the NGS call looks real we do not have a S anger primer pair where both primers are unique. The origin of this variant can not be unambiguously assigned and therefore it is excluded from patient reports. LMM is in the process of exuding repetitive regions where Sanger confirmation is not possible from tests (pending). p.Val34Ala in exon 3 of SFTPA1: This var iant was detected at high frequency in large cohorts sequenced by the ExAC conso rtium (http://exac.broadinstitute.org/). While the frequencies are high enough to rule out a pathogneic role the data did not pass quality filters. Other data supporting a benign role include to a lack of conservation across species, inclu ding mammals. Of note, the gorilla, orangutan, gibbon, rhesus, crab eating macaq ue, baboon, and green monkey have an alanine (Ala) at this position. In additio n, computational prediction tools do not suggest a high likelihood of impact to the protein. -

See cases Benign:1

Likely benign, no assertion criteria provided

case-control

Department of Pediatrics, Penn State Hershey College of Medicine

-

- -

SFTPA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0045	N
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.10	N;N;N;N;N
REVEL	Benign	0.027
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	0.84	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.074
MPC		0.017
ClinPred		0.0064	T
GERP RS		-5.3
Varity_R		0.018
gMVP		0.15

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

LitVar

Other links and lift over

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