10-79611798-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005411.5(SFTPA1):​c.-23-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,461,868 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0085 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: SFTPA1 NM_005411.5 splice_region, intron
• Scores: Splicing: ADA: 0.03134
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-79611798-T-G is Benign according to our data. Variant chr10-79611798-T-G is described in ClinVar as Benign. ClinVar VariationId is 3350749.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00853 (1055/123736) while in subpopulation AFR AF = 0.0281 (1001/35560). AF 95% confidence interval is 0.0267. There are 13 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA1	NM_005411.5	MANE Select	c.-23-5T>G		splice_region intron	N/A	NP_005402.3
	SFTPA1	NM_001093770.3		c.23-5T>G		splice_region intron	N/A	NP_001087239.2	Q8IWL2-2
	SFTPA1	NM_001164644.2		c.-23-5T>G		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>G		splice_region intron	N/A	ENSP00000381633.3	Q8IWL2-1
	SFTPA1	ENST00000419470.6	TSL:1	c.23-5T>G		splice_region intron	N/A	ENSP00000397082.2	Q8IWL2-2
	SFTPA1	ENST00000428376.6	TSL:1	c.-23-5T>G		splice_region intron	N/A	ENSP00000411102.2	Q8IWL2-1

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 1048 AN: 123628 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00228

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000484

Gnomad SAS AF: 0.000261

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00800

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00777

GnomAD2 exomes AF: 0.00230 AC: 364 AN: 158420 AF XY: 0.00162

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000161

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.000663 AC: 887 AN: 1338132 Hom.: 1 Cov.: 105 AF XY: 0.000576 AC XY: 383 AN XY: 664634

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

African (AFR) AF: 0.0224 AC: 691 AN: 30856

American (AMR) AF: 0.00131 AC: 51 AN: 38890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35464

South Asian (SAS) AF: 0.000102 AC: 8 AN: 78614

European-Finnish (FIN) AF: 0.0000213 AC: 1 AN: 46946

Middle Eastern (MID) AF: 0.00155 AC: 8 AN: 5164

European-Non Finnish (NFE) AF: 0.0000459 AC: 47 AN: 1024442

Other (OTH) AF: 0.00148 AC: 81 AN: 54584

⚠️ 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: 0.00853 AC: 1055 AN: 123736 Hom.: 13 Cov.: 33 AF XY: 0.00839 AC XY: 508 AN XY: 60530

African (AFR) AF: 0.0281 AC: 1001 AN: 35560

American (AMR) AF: 0.00228 AC: 28 AN: 12306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2908

East Asian (EAS) AF: 0.000484 AC: 2 AN: 4130

South Asian (SAS) AF: 0.000262 AC: 1 AN: 3818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8352

Middle Eastern (MID) AF: 0.00847 AC: 2 AN: 236

European-Non Finnish (NFE) AF: 0.000148 AC: 8 AN: 54022

Other (OTH) AF: 0.00767 AC: 13 AN: 1696

Alfa AF: 0.000304 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	-0.83
CADD	Benign	1.1
DANN	Benign	0.65
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.031
dbscSNV1_RF	Benign	0.24
SpliceAI score (max)		0.14		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: rs3997775; hg19: chr10-81371554;