rs192907309

Variant names:

• chr10-79559336-C-G
• rs192907309
• NM_001098668.4:c.148G>C

Your query was ambiguous. Multiple possible variants found:

• chr10-79559336-C-G
• chr10-79559336-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000372325.7(SFTPA2):​c.148G>C​(p.Val50Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,531,982 control chromosomes in the GnomAD database, including 2,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (173 hom., cov: 28)
  • Exomes 𝑓: 0.023 (2528 hom.)
• Consequence: SFTPA2 ENST00000372325.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82
• Publications: 9 publications found

Genes affected

SFTPA2 (HGNC:10799): (surfactant protein A2) This gene is one of several genes encoding pulmonary-surfactant associated proteins (SFTPA) located on chromosome 10. Mutations in this gene and a highly similar gene located nearby, which affect the highly conserved carbohydrate recognition domain, are associated with idiopathic pulmonary fibrosis. The current version of the assembly displays only a single centromeric SFTPA gene pair rather than the two gene pairs shown in the previous assembly which were thought to have resulted from a duplication. [provided by RefSeq, Sep 2009]

SFTPA2 Gene-Disease associations (from GenCC):

• interstitial lung disease 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• idiopathic pulmonary fibrosis

  Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046575665).
• BP6: Variant 10-79559336-C-G is Benign according to our data. Variant chr10-79559336-C-G is described in ClinVar as Benign. ClinVar VariationId is 227065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.061 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000372325.7. 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
	SFTPA2	NM_001098668.4	MANE Select	c.148G>C	p.Val50Leu	missense	Exon 3 of 6	NP_001092138.1
	SFTPA2	NM_001320814.1		c.178G>C	p.Val60Leu	missense	Exon 2 of 5	NP_001307743.1
	SFTPA2	NM_001320813.2		c.148G>C	p.Val50Leu	missense	Exon 3 of 6	NP_001307742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPA2	ENST00000372325.7	TSL:1 MANE Select	c.148G>C	p.Val50Leu	missense	Exon 3 of 6	ENSP00000361400.2
	SFTPA2	ENST00000372327.9	TSL:1	c.148G>C	p.Val50Leu	missense	Exon 2 of 5	ENSP00000361402.5
	SFTPA2	ENST00000417041.1	TSL:5	c.148G>C	p.Val50Leu	missense	Exon 3 of 6	ENSP00000397375.1

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6255 AN: 151814 Hom.: 172 Cov.: 28

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.0558

Gnomad EAS AF: 0.00580

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0625

Gnomad OTH AF: 0.0490

GnomAD2 exomes AF: 0.0247 AC: 5945 AN: 241058 AF XY: 0.0265

Gnomad AFR exome AF: 0.00751

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0413

Gnomad EAS exome AF: 0.00267

Gnomad FIN exome AF: 0.0119

Gnomad NFE exome AF: 0.0323

Gnomad OTH exome AF: 0.0305

GnomAD4 exome AF: 0.0233 AC: 32182 AN: 1380050 Hom.: 2528 Cov.: 32 AF XY: 0.0247 AC XY: 16998 AN XY: 687524

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

African (AFR) AF: 0.00806 AC: 267 AN: 33122

American (AMR) AF: 0.0214 AC: 946 AN: 44154

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 1073 AN: 25324

East Asian (EAS) AF: 0.00255 AC: 101 AN: 39666

South Asian (SAS) AF: 0.0373 AC: 3123 AN: 83770

European-Finnish (FIN) AF: 0.0247 AC: 1292 AN: 52410

Middle Eastern (MID) AF: 0.0503 AC: 277 AN: 5506

European-Non Finnish (NFE) AF: 0.0226 AC: 23471 AN: 1038132

Other (OTH) AF: 0.0282 AC: 1632 AN: 57966

⚠️ 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: 0.0412 AC: 6256 AN: 151932 Hom.: 173 Cov.: 28 AF XY: 0.0399 AC XY: 2963 AN XY: 74258

African (AFR) AF: 0.0132 AC: 548 AN: 41510

American (AMR) AF: 0.0334 AC: 510 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0558 AC: 193 AN: 3458

East Asian (EAS) AF: 0.00601 AC: 31 AN: 5158

South Asian (SAS) AF: 0.0419 AC: 201 AN: 4802

European-Finnish (FIN) AF: 0.0340 AC: 360 AN: 10576

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0625 AC: 4243 AN: 67862

Other (OTH) AF: 0.0480 AC: 101 AN: 2104

Alfa AF: 0.0315 Hom.: 25

Bravo AF: 0.0398

ExAC AF: 0.0400 AC: 4860

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.034
DANN	Benign	0.71
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.94	T
PhyloP100		-1.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.027
Sift	Benign	0.69	T
Sift4G	Benign	0.47	T
Vest4		0.049
MPC		1.6
ClinPred		0.0026	T
GERP RS		-4.2
PromoterAI		-0.017	Neutral
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs192907309; hg19: chr10-81319092; COSMIC: COSV64882108; COSMIC: COSV64882108;