10-79614090-C-T

Variant names:

• chr10-79614090-C-T
• rs4253528
• NM_005411.5:c.724C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005411.5(SFTPA1):​c.724C>T​(p.Arg242*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,064 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (1 hom.)
• Consequence: SFTPA1 NM_005411.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.31
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

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.724C>T	p.Arg242*	stop_gained	Exon 6 of 6	NP_005402.3
	SFTPA1	NM_001093770.3		c.769C>T	p.Arg257*	stop_gained	Exon 6 of 6	NP_001087239.2
	SFTPA1	NM_001164644.2		c.724C>T	p.Arg242*	stop_gained	Exon 6 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.724C>T	p.Arg242*	stop_gained	Exon 6 of 6	ENSP00000381633.3
	SFTPA1	ENST00000419470.6	TSL:1	c.769C>T	p.Arg257*	stop_gained	Exon 6 of 6	ENSP00000397082.2
	SFTPA1	ENST00000428376.6	TSL:1	c.724C>T	p.Arg242*	stop_gained	Exon 5 of 5	ENSP00000411102.2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251424 AF XY: 0.0000662

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461872 Hom.: 1 Cov.: 32 AF XY: 0.0000605 AC XY: 44 AN XY: 727238

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111998

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

African (AFR) AF: 0.0000965 AC: 4 AN: 41458

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg257X variant in SFTPA1 has not been previously reported in individuals with pulmonary disease, but has been identified in 22/277174 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs4 253528). This nonsense variant leads to a premature termination codon at positio n 257. This alteration occurs within the last exon of the gene and is more likel y to escape nonsense mediated decay (NMD) and result in a truncated protein. Due to the limited information available regarding the association of this gene to disease, it is unknown if this type of variant is likely to be disease-causing. Therefore, the clinical significance of the p.Arg257X variant is uncertain.

Respiratory distress associated with prematurity Uncertain:1

Jul 02, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This SFTPA1 variant (rs4253528) is present in large population datasets (gnomAD: 21/282816 total alleles; 0.007425%; no homozygotes). A single submitter in ClinVar classifies this variant as uncertain. This nonsense variant is located in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. Due to insufficient evidence that this variant is deleterious, the clinical significance of c.724C>T is uncertain at this time.

Interstitial lung disease 1 Uncertain:1

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.12	N
PhyloP100		1.3
Vest4		0.70
GERP RS		2.0
Mutation Taster		=65/135	disease causing

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: rs4253528; hg19: chr10-81373846; COSMIC: COSV105296244; COSMIC: COSV105296244;