rs72824125

Variant names:

• chr2-48580986-G-A
• rs72824125
• NM_006873.4:c.353G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-48580986-G-A
• chr2-48580986-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006873.4(STON1):​c.353G>A​(p.Gly118Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G118V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: STON1 NM_006873.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1060707).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STON1	NM_006873.4	c.353G>A	p.Gly118Glu	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.353G>A	p.Gly118Glu	missense_variant	Exon 2 of 4	1	NM_006873.4	ENSP00000385273.1
STON1-GTF2A1L	ENST00000394754.5	c.353G>A	p.Gly118Glu	missense_variant	Exon 2 of 11	1		ENSP00000378236.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423622 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 705112

African (AFR) AF: 0.00 AC: 0 AN: 32240

American (AMR) AF: 0.00 AC: 0 AN: 38174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23370

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.00 AC: 0 AN: 77982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096142

Other (OTH) AF: 0.00 AC: 0 AN: 58774

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.86
DANN	Benign	0.88
DEOGEN2	Benign	0.033	T;T;T;.;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.58	.;.;T;.;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;.;.;.;.
PhyloP100		0.28
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	.;N;N;N;N;N;N
REVEL	Benign	0.023
Sift	Uncertain	0.0020	.;D;D;D;D;D;D
Sift4G	Uncertain	0.028	.;D;D;D;D;D;D
Polyphen		0.0040	B;B;B;B;.;B;.
Vest4		0.16, 0.19, 0.14, 0.20, 0.19
MutPred		0.18		Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);
MVP		0.28
MPC		0.0032
ClinPred		0.16	T
GERP RS		1.9
PromoterAI		0.0020	Neutral
Varity_R		0.061
gMVP		0.25
Mutation Taster		=98/2	polymorphism

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

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Other links and lift over

dbSNP: rs72824125; hg19: chr2-48808125; COSMIC: COSV104624809; COSMIC: COSV104624809;