rs764841861

Positions:

• chr7-100204096-C-G
• chr7-100204096-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001282717.2(STAG3):​c.2776C>G​(p.Arg926Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: STAG3 NM_001282717.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71

Genes affected

STAG3 (HGNC:11356): (STAG3 cohesin complex component) The protein encoded by this gene is expressed in the nucleus and is a subunit of the cohesin complex which regulates the cohesion of sister chromatids during cell division. A mutation in this gene is associated with premature ovarian failure. Alternate splicing results in multiple transcript variants encoding distinct isoforms. This gene has multiple pseudogenes. [provided by RefSeq, Apr 2014]

CASTOR3P (HGNC:29954): (CASTOR family member 3, pseudogene) Predicted to be involved in cellular response to L-arginine and negative regulation of TORC1 signaling. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), STAG3. . Gene score misZ 1.6577 (greater than the threshold 3.09). Trascript score misZ 3.2175 (greater than threshold 3.09). GenCC has associacion of gene with spermatogenic failure 61, premature ovarian failure 8.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17158628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAG3	NM_001282717.2	c.2776C>G	p.Arg926Gly	missense_variant	26/34	ENST00000615138.5	NP_001269646.1
CASTOR3P	NR_028040.1	n.914-1493G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAG3	ENST00000615138.5	c.2776C>G	p.Arg926Gly	missense_variant	26/34	1	NM_001282717.2	ENSP00000477973	A2
CASTOR3P	ENST00000649671.1	n.776-1493G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.66	.;.;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.5	D;D;.;.;D
REVEL	Benign	0.077
Sift	Benign	0.045	D;T;.;.;D
Sift4G	Uncertain	0.031	D;D;D;D;D
Polyphen		0.0020	B;.;.;B;B
Vest4		0.36
MutPred		0.46		Loss of MoRF binding (P = 0.0419);.;.;Loss of MoRF binding (P = 0.0419);Loss of MoRF binding (P = 0.0419);
MVP		0.34
MPC		0.17
ClinPred		0.54	D
GERP RS		2.8
Varity_R		0.13
gMVP		0.42

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: rs764841861; hg19: chr7-99801719;