rs3997775

Variant names:

• chr10-79611798-T-A
• rs3997775
• NM_005411.5:c.-23-5T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-79611798-T-A
• chr10-79611798-T-C
• chr10-79611798-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BP6

The NM_005411.5(SFTPA1):​c.-23-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.21 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: SFTPA1 NM_005411.5 splice_region, intron
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.30
• Publications: 3 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 Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 10-79611798-T-A is Benign according to our data. Variant chr10-79611798-T-A is described in ClinVar as Benign. ClinVar VariationId is 3355976.Status of the report is no_assertion_criteria_provided, 0 stars.

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.-23-5T>A		splice_region intron	N/A	NP_005402.3
	SFTPA1	NM_001093770.3		c.23-5T>A		splice_region intron	N/A	NP_001087239.2	Q8IWL2-2
	SFTPA1	NM_001164644.2		c.-23-5T>A		splice_region intron	N/A	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.-23-5T>A		splice_region intron	N/A	ENSP00000381633.3	Q8IWL2-1
	SFTPA1	ENST00000419470.6	TSL:1	c.23-5T>A		splice_region intron	N/A	ENSP00000397082.2	Q8IWL2-2
	SFTPA1	ENST00000428376.6	TSL:1	c.-23-5T>A		splice_region intron	N/A	ENSP00000411102.2	Q8IWL2-1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 1596 AN: 107188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00899

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00418

Gnomad EAS AF: 0.0257

Gnomad SAS AF: 0.00981

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0176

GnomAD2 exomes AF: 0.189 AC: 29871 AN: 158420 AF XY: 0.199

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.141

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.203

Gnomad NFE exome AF: 0.243

Gnomad OTH exome AF: 0.157

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.206 AC: 181168 AN: 877824 Hom.: 5 Cov.: 105 AF XY: 0.197 AC XY: 86314 AN XY: 439148

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

African (AFR) AF: 0.0691 AC: 1628 AN: 23544

American (AMR) AF: 0.0670 AC: 1846 AN: 27558

Ashkenazi Jewish (ASJ) AF: 0.0569 AC: 985 AN: 17302

East Asian (EAS) AF: 0.0690 AC: 1861 AN: 26962

South Asian (SAS) AF: 0.0582 AC: 3376 AN: 57962

European-Finnish (FIN) AF: 0.0396 AC: 1356 AN: 34258

Middle Eastern (MID) AF: 0.0528 AC: 211 AN: 3994

European-Non Finnish (NFE) AF: 0.253 AC: 164276 AN: 648838

Other (OTH) AF: 0.150 AC: 5629 AN: 37406

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0149 AC: 1594 AN: 107304 Hom.: 0 Cov.: 33 AF XY: 0.0160 AC XY: 838 AN XY: 52510

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

African (AFR) AF: 0.0125 AC: 409 AN: 32712

American (AMR) AF: 0.0124 AC: 134 AN: 10850

Ashkenazi Jewish (ASJ) AF: 0.00418 AC: 11 AN: 2634

East Asian (EAS) AF: 0.0257 AC: 88 AN: 3420

South Asian (SAS) AF: 0.00981 AC: 33 AN: 3364

European-Finnish (FIN) AF: 0.0412 AC: 276 AN: 6706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.0135 AC: 612 AN: 45360

Other (OTH) AF: 0.0173 AC: 26 AN: 1502

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0874 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	SFTPA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.68
PhyloP100		-1.3
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.65		Position offset: 2
DS_AL_spliceai		0.31		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3997775; hg19: chr10-81371554; COSMIC: COSV64866565;