rs4253526

Positions:

• chr10-79613918-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005411.5(SFTPA1):​c.552T>C​(p.Tyr184Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0188 in 1,613,958 control chromosomes in the GnomAD database, including 1,927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (239 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1688 hom.)
• Consequence: SFTPA1 NM_005411.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.97

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-79613918-T-C is Benign according to our data. Variant chr10-79613918-T-C is described in ClinVar as [Benign]. Clinvar id is 165200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPA1	NM_005411.5	c.552T>C	p.Tyr184Tyr	synonymous_variant	6/6	ENST00000398636.8	NP_005402.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPA1	ENST00000398636.8	c.552T>C	p.Tyr184Tyr	synonymous_variant	6/6	1	NM_005411.5	ENSP00000381633.3
SFTPA1	ENST00000419470.6	c.597T>C	p.Tyr199Tyr	synonymous_variant	6/6	1		ENSP00000397082.2
SFTPA1	ENST00000428376.6	c.552T>C	p.Tyr184Tyr	synonymous_variant	5/5	1		ENSP00000411102.2

Frequencies

GnomAD3 genomes AF: 0.0251 AC: 3823 AN: 152174 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0445

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.0886

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00456

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0422 AC: 10604 AN: 251200 Hom.: 868 AF XY: 0.0415 AC XY: 5636 AN XY: 135768

Gnomad AFR exome AF: 0.0239

Gnomad AMR exome AF: 0.0664

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.261

Gnomad SAS exome AF: 0.0778

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0182 AC: 26551 AN: 1461666 Hom.: 1688 Cov.: 33 AF XY: 0.0195 AC XY: 14155 AN XY: 727146

Gnomad4 AFR exome AF: 0.0248

Gnomad4 AMR exome AF: 0.0649

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.0745

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.0296

GnomAD4 genome AF: 0.0251 AC: 3828 AN: 152292 Hom.: 239 Cov.: 32 AF XY: 0.0275 AC XY: 2050 AN XY: 74464

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.248

Gnomad4 SAS AF: 0.0881

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00456

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.00903 Hom.: 8

Bravo AF: 0.0275

EpiCase AF: 0.00485

EpiControl AF: 0.00516

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Tyr199Tyr in exon 6 of SFTPA1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 2.6% (115/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs148138544). -

SFTPA1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.073
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs4253526; hg19: chr10-81373674; COSMIC: COSV64867164; COSMIC: COSV64867164;