7-100180880-GTTTTT-GTTT

Variant names:

• chr7-100180880-GTT-G
• rs35965210
• NM_001282717.2:c.116+224_116+225delTT

Variant summary

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

The NM_001282717.2(STAG3):​c.116+224_116+225delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0079 in 220,540 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 27)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: STAG3 NM_001282717.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.666
• Publications: 0 publications found

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]

STAG3 Gene-Disease associations (from GenCC):

• premature ovarian failure 8

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• spermatogenic failure 61

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0204) population. However there is too low homozygotes in high coverage region: (expected more than 3, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282717.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAG3	NM_001282717.2	MANE Select	c.116+224_116+225delTT		intron	N/A	NP_001269646.1	D6W5U7
	STAG3	NM_001375438.1		c.116+224_116+225delTT		intron	N/A	NP_001362367.1	D6W5U7
	STAG3	NM_001282716.1		c.116+224_116+225delTT		intron	N/A	NP_001269645.1	Q9UJ98-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAG3	ENST00000615138.5	TSL:1 MANE Select	c.116+200_116+201delTT		intron	N/A	ENSP00000477973.1	D6W5U7
	STAG3	ENST00000317296.9	TSL:1	c.116+200_116+201delTT		intron	N/A	ENSP00000319318.5	Q9UJ98-1
	STAG3	ENST00000426455.5	TSL:1	c.116+200_116+201delTT		intron	N/A	ENSP00000400359.1	Q9UJ98-1

Frequencies

GnomAD3 genomes AF: 0.0000439 AC: 6 AN: 136812 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000744

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000402

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000317

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0207 AC: 1737 AN: 83726 Hom.: 0 AF XY: 0.0204 AC XY: 929 AN XY: 45514

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0183 AC: 35 AN: 1908

American (AMR) AF: 0.0244 AC: 75 AN: 3072

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 45 AN: 2090

East Asian (EAS) AF: 0.0206 AC: 100 AN: 4844

South Asian (SAS) AF: 0.0227 AC: 257 AN: 11318

European-Finnish (FIN) AF: 0.0191 AC: 98 AN: 5142

Middle Eastern (MID) AF: 0.0110 AC: 3 AN: 272

European-Non Finnish (NFE) AF: 0.0204 AC: 1021 AN: 50166

Other (OTH) AF: 0.0210 AC: 103 AN: 4914

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000439 AC: 6 AN: 136814 Hom.: 0 Cov.: 27 AF XY: 0.0000457 AC XY: 3 AN XY: 65580

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37438

American (AMR) AF: 0.0000743 AC: 1 AN: 13462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3286

East Asian (EAS) AF: 0.00 AC: 0 AN: 4734

South Asian (SAS) AF: 0.00 AC: 0 AN: 4274

European-Finnish (FIN) AF: 0.000402 AC: 3 AN: 7466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.0000317 AC: 2 AN: 63178

Other (OTH) AF: 0.00 AC: 0 AN: 1856

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000717941), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.67
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs35965210; hg19: chr7-99778503;