Genetic Variant NM_006873.4:c.44A>G (chr2-48580677-A-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006873.4(STON1):c.44A>G(p.Asp15Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000785 in 1,273,214 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D15V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

STON1
NM_006873.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.53

Variant links:

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 links:

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]

STON1-GTF2A1L links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31930143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STON1	NM_006873.4 link	c.44A>G	p.Asp15Gly	missense_variant	Exon 2 of 4	ENST00000404752.6	NP_006864.2	Q9Y6Q2-1B2RB25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STON1	ENST00000404752.6 link	c.44A>G	p.Asp15Gly	missense_variant	Exon 2 of 4	1	NM_006873.4	ENSP00000385273.1		Q9Y6Q2-1
STON1-GTF2A1L	ENST00000394754.5 link	c.44A>G	p.Asp15Gly	missense_variant	Exon 2 of 11	1		ENSP00000378236.1		Q53S48

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.85e-7

AC:

AN:

1273214

Hom.:

Cov.:

AF XY:

0.00000162

AC XY:

AN XY:

617626

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27098

American (AMR)

AF:

0.00

AC:

AN:

21142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18156

East Asian (EAS)

AF:

0.00

AC:

AN:

33182

South Asian (SAS)

AF:

0.00

AC:

AN:

50502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5014

European-Non Finnish (NFE)

AF:

9.82e-7

AC:

AN:

1018416

Other (OTH)

AF:

0.00

AC:

AN:

52096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.049

T;T;T;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;.;D;.;D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.32

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;M;.;.;.;.

PhyloP100

8.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

.;N;N;N;N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0020

.;D;D;D;D;D;D

Sift4G

Uncertain

0.0080

.;D;D;D;D;D;D

Polyphen

0.88

P;P;P;D;.;D;.

Vest4

0.42, 0.42, 0.45, 0.41, 0.44, 0.46

MVP

0.62

MPC

0.012

ClinPred

0.93

GERP RS

5.3

PromoterAI

-0.013

Neutral

(source)

Varity_R

0.27

gMVP

0.34

Mutation Taster

=67/33

polymorphism

(source)

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over