NM_005411.5:c.26A>C

Variant names:

• chr10-79611851-A-C
• rs139899873
• NM_005411.5:c.26A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (25 hom., cov: 34)
  • Exomes 𝑓: 0.00085 (19 hom.)
• Consequence: SFTPA1 NM_005411.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.57
• Publications: 5 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]

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 227944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA1	NM_005411.5	MANE Select	c.26A>C	p.Asn9Thr	missense	Exon 3 of 6	NP_005402.3
	SFTPA1	NM_001093770.3		c.71A>C	p.Asn24Thr	missense	Exon 3 of 6	NP_001087239.2
	SFTPA1	NM_001164644.2		c.26A>C	p.Asn9Thr	missense	Exon 3 of 6	NP_001158116.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA1	ENST00000398636.8	TSL:1 MANE Select	c.26A>C	p.Asn9Thr	missense	Exon 3 of 6	ENSP00000381633.3
	SFTPA1	ENST00000419470.6	TSL:1	c.71A>C	p.Asn24Thr	missense	Exon 3 of 6	ENSP00000397082.2
	SFTPA1	ENST00000428376.6	TSL:1	c.26A>C	p.Asn9Thr	missense	Exon 2 of 5	ENSP00000411102.2

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

GnomAD2 exomes AF: 0.00121 AC: 304 AN: 250754 AF XY: 0.000885

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 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

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

African (AFR) AF: 0.0275 AC: 918 AN: 33372

American (AMR) AF: 0.00150 AC: 67 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86250

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.0000756 AC: 84 AN: 1111792

Other (OTH) AF: 0.00244 AC: 147 AN: 60366

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

African (AFR) AF: 0.0283 AC: 1175 AN: 41474

American (AMR) AF: 0.00373 AC: 57 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.000060	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-1.6
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.016
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs139899873; hg19: chr10-81371607;