3-49684099-G-A

Variant names:

• chr3-49684099-G-A
• rs3197999
• NM_020998.4:c.2107C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020998.4(MST1):​c.2107C>T​(p.Arg703Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,612,770 control chromosomes in the GnomAD database, including 65,085 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R703H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5799 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59286 hom.)
• Consequence: MST1 NM_020998.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12

Genes affected

MST1 (HGNC:7380): (macrophage stimulating 1) The protein encoded by this gene contains four kringle domains and a serine protease domain, similar to that found in hepatic growth factor. Despite the presence of the serine protease domain, the encoded protein may not have any proteolytic activity. The receptor for this protein is RON tyrosine kinase, which upon activation stimulates ciliary motility of ciliated epithelial lung cells. This protein is secreted and cleaved to form an alpha chain and a beta chain bridged by disulfide bonds. [provided by RefSeq, Jan 2010]

APEH (HGNC:586): (acylaminoacyl-peptide hydrolase) This gene encodes the enzyme acylpeptide hydrolase, which catalyzes the hydrolysis of the terminal acetylated amino acid preferentially from small acetylated peptides. The acetyl amino acid formed by this hydrolase is further processed to acetate and a free amino acid by an aminoacylase. This gene is located within the same region of chromosome 3 (3p21) as the aminoacylase gene, and deletions at this locus are also associated with a decrease in aminoacylase activity. The acylpeptide hydrolase is a homotetrameric protein of 300 kDa with each subunit consisting of 732 amino acid residues. It can play an important role in destroying oxidatively damaged proteins in living cells. Deletions of this gene locus are found in various types of carcinomas, including small cell lung carcinoma and renal cell carcinoma. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004493147).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MST1	NM_020998.4	c.2107C>T	p.Arg703Cys	missense_variant	Exon 18 of 18	ENST00000449682.3	NP_066278.3
APEH	NM_001640.4	c.*757G>A		downstream_gene_variant		ENST00000296456.10	NP_001631.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MST1	ENST00000449682.3	c.2107C>T	p.Arg703Cys	missense_variant	Exon 18 of 18	1	NM_020998.4	ENSP00000414287.2
APEH	ENST00000296456.10	c.*757G>A		downstream_gene_variant		1	NM_001640.4	ENSP00000296456.5

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40118 AN: 152004 Hom.: 5798 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.443

Gnomad EAS AF: 0.0451

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.257 AC: 64425 AN: 250726 AF XY: 0.260

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.0453

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.291

Gnomad OTH exome AF: 0.283

GnomAD4 exome AF: 0.277 AC: 405087 AN: 1460650 Hom.: 59286 Cov.: 39 AF XY: 0.276 AC XY: 200855 AN XY: 726644

Gnomad4 AFR exome AF: 0.233 AC: 7805 AN: 33468

Gnomad4 AMR exome AF: 0.151 AC: 6740 AN: 44696

Gnomad4 ASJ exome AF: 0.439 AC: 11459 AN: 26092

Gnomad4 EAS exome AF: 0.0436 AC: 1730 AN: 39658

Gnomad4 SAS exome AF: 0.227 AC: 19557 AN: 86228

Gnomad4 FIN exome AF: 0.409 AC: 21739 AN: 53112

Gnomad4 NFE exome AF: 0.286 AC: 317391 AN: 1111292

Gnomad4 Remaining exome AF: 0.281 AC: 16943 AN: 60346

GnomAD4 genome AF: 0.264 AC: 40134 AN: 152120 Hom.: 5799 Cov.: 33 AF XY: 0.266 AC XY: 19756 AN XY: 74364

Gnomad4 AFR AF: 0.231 AC: 0.231496 AN: 0.231496

Gnomad4 AMR AF: 0.202 AC: 0.202353 AN: 0.202353

Gnomad4 ASJ AF: 0.443 AC: 0.442651 AN: 0.442651

Gnomad4 EAS AF: 0.0452 AC: 0.0452087 AN: 0.0452087

Gnomad4 SAS AF: 0.209 AC: 0.209457 AN: 0.209457

Gnomad4 FIN AF: 0.424 AC: 0.423689 AN: 0.423689

Gnomad4 NFE AF: 0.284 AC: 0.284245 AN: 0.284245

Gnomad4 OTH AF: 0.278 AC: 0.277673 AN: 0.277673

Alfa AF: 0.275 Hom.: 24848

Bravo AF: 0.245

TwinsUK AF: 0.297 AC: 1101

ALSPAC AF: 0.279 AC: 1075

ESP6500AA AF: 0.235 AC: 1036

ESP6500EA AF: 0.294 AC: 2525

ExAC AF: 0.255 AC: 30977

Asia WGS AF: 0.128 AC: 451 AN: 3478

EpiCase AF: 0.294

EpiControl AF: 0.291

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.045	D
Polyphen		0.73	P
Vest4		0.35
MPC		0.46
ClinPred		0.025	T
GERP RS		-2.8
gMVP		0.76
Mutation Taster		=96/4	polymorphism (auto)

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: rs3197999; hg19: chr3-49721532; COSMIC: COSV56532741; COSMIC: COSV56532741;