10-79611851-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005411.5(SFTPA1):c.26A>C(p.Asn9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,613,692 control chromosomes in the GnomAD database, including 44 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 0.0083 (25 hom., cov: 34)
  • Exomes 𝑓: 0.00085 (19 hom.)
• Consequence: SFTPA1 NM_005411.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.57

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040893555).
• BP6: Variant 10-79611851-A-C is Benign according to our data. Variant chr10-79611851-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 227944.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00827 (1259/152210) while in subpopulation AFR AF= 0.0283 (1175/41474). AF 95% confidence interval is 0.027. There are 25 homozygotes in gnomad4. There are 557 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SFTPA1	NM_005411.5	c.26A>C	p.Asn9Thr	missense_variant	3/6	ENST00000398636.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SFTPA1	ENST00000398636.8	c.26A>C	p.Asn9Thr	missense_variant	3/6	1	NM_005411.5	P1

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1255 AN: 152094 Hom.: 23 Cov.: 34

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00121 AC: 304 AN: 250754 Hom.: 3 AF XY: 0.000885 AC XY: 120 AN XY: 135592

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000850 AC: 1242 AN: 1461482 Hom.: 19 Cov.: 124 AF XY: 0.000722 AC XY: 525 AN XY: 727060

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.00244

GnomAD4 genome AF: 0.00827 AC: 1259 AN: 152210 Hom.: 25 Cov.: 34 AF XY: 0.00748 AC XY: 557 AN XY: 74444

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00436 Hom.: 1

Bravo AF: 0.00984

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00200 AC: 243

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 16, 2015

p.Asn24Thr in exon 3 of SFTPA1: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >10 mammals have a threonine (Thr) at this position. In addition, computati onal prediction tools do not suggest a high likelihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.030
Dann	Benign	0.16
DEOGEN2	Benign	0.043	T;T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.000060	N
MetaRNN	Benign	0.0041	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.2	N;N;N;N;N
REVEL	Benign	0.016
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.11
MVP		0.055
MPC		0.017
ClinPred		0.0061	T
GERP RS		1.6
Varity_R		0.029
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs139899873; hg19: chr10-81371607;