rs940389

Variant names:

• chr2-48581013-G-C
• rs940389
• NM_006873.4:c.380G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006873.4(STON1):​c.380G>C​(p.Arg127Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,568,372 control chromosomes in the GnomAD database, including 92,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (9047 hom., cov: 32)
  • Exomes 𝑓: 0.34 (83154 hom.)
• Consequence: STON1 NM_006873.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

Genes affected

STON1 (HGNC:17003): (stonin 1) Endocytosis of cell surface proteins is mediated by a complex molecular machinery that assembles on the inner surface of the plasma membrane. This gene encodes one of two human homologs of the Drosophila melanogaster stoned B protein. This protein is related to components of the endocytic machinery and exhibits a modular structure consisting of an N-terminal proline-rich domain, a central region of homology specific to the human stoned B-like proteins, and a C-terminal region homologous to the mu subunits of adaptor protein (AP) complexes. Read-through transcription of this gene into the neighboring downstream gene, which encodes TFIIA-alpha/beta-like factor, generates a transcript (SALF), which encodes a fusion protein comprised of sequence sharing identity with each individual gene product. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

STON1-GTF2A1L (HGNC:30651): (STON1-GTF2A1L readthrough) STON1-GTF2A1L mRNAs are infrequent but naturally occurring read-through products of the neighboring STON1 and GTF2A1L genes. These transcripts encode fusion proteins composed of the vast majority of each of the individual elements, stonin 1 and general transcription factor IIA, 1-like. Alternative splicing results in multiple transcript variants. The significance of these read-through variants and the function of the resulting protein products have not yet been determined. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010421574).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STON1	NM_006873.4	c.380G>C	p.Arg127Thr	missense_variant	Exon 2 of 4	ENST00000404752.6	NP_006864.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STON1	ENST00000404752.6	c.380G>C	p.Arg127Thr	missense_variant	Exon 2 of 4	1	NM_006873.4	ENSP00000385273.1
STON1-GTF2A1L	ENST00000394754.5	c.380G>C	p.Arg127Thr	missense_variant	Exon 2 of 11	1		ENSP00000378236.1

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51916 AN: 151902 Hom.: 9034 Cov.: 32

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.328

GnomAD3 exomes AF: 0.354 AC: 73319 AN: 206930 Hom.: 13459 AF XY: 0.357 AC XY: 39456 AN XY: 110532

Gnomad AFR exome AF: 0.316

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.414

Gnomad FIN exome AF: 0.458

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.339 AC: 480750 AN: 1416352 Hom.: 83154 Cov.: 40 AF XY: 0.342 AC XY: 239608 AN XY: 700940

Gnomad4 AFR exome AF: 0.315

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.331

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.342 AC: 51978 AN: 152020 Hom.: 9047 Cov.: 32 AF XY: 0.348 AC XY: 25880 AN XY: 74280

Gnomad4 AFR AF: 0.320

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.331

Alfa AF: 0.331 Hom.: 5359

Bravo AF: 0.325

TwinsUK AF: 0.343 AC: 1273

ALSPAC AF: 0.320 AC: 1235

ESP6500AA AF: 0.318 AC: 1400

ESP6500EA AF: 0.332 AC: 2852

ExAC AF: 0.348 AC: 42114

Asia WGS AF: 0.422 AC: 1455 AN: 3454

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.3
DANN	Benign	0.70
DEOGEN2	Benign	0.0039	T;T;T;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.32	.;.;T;.;T;T;T
MetaRNN	Benign	0.0010	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N;N;N;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.29	.;N;N;N;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.030	.;D;D;D;D;D;D
Sift4G	Uncertain	0.012	.;D;D;D;D;D;D
Polyphen		0.039	B;B;B;B;.;B;.
Vest4		0.12, 0.11, 0.13, 0.13, 0.13, 0.13
MPC		0.0029
ClinPred		0.0026	T
GERP RS		2.8
Varity_R		0.031
gMVP		0.21

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: rs940389; hg19: chr2-48808152; COSMIC: COSV59127318; COSMIC: COSV59127318;