7-100180880-GTTTTT-GTTTTTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS1

The NM_001282717.2(STAG3):​c.116+224_116+225dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 220,142 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00094 (1 hom., cov: 27)
  • Exomes 𝑓: 0.053 (0 hom.)
• Consequence: STAG3 NM_001282717.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Variant has high frequency in the MID (0.0526) population. However there is too low homozygotes in high coverage region: (expected more than 23, got 1).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000943 (129/136822) while in subpopulation SAS AF = 0.00117 (5/4274). AF 95% confidence interval is 0.000757. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

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+225dupTT		intron	N/A	NP_001269646.1	D6W5U7
	STAG3	NM_001375438.1		c.116+224_116+225dupTT		intron	N/A	NP_001362367.1	D6W5U7
	STAG3	NM_001282716.1		c.116+224_116+225dupTT		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+201_116+202insTT		intron	N/A	ENSP00000477973.1	D6W5U7
	STAG3	ENST00000317296.9	TSL:1	c.116+201_116+202insTT		intron	N/A	ENSP00000319318.5	Q9UJ98-1
	STAG3	ENST00000426455.5	TSL:1	c.116+201_116+202insTT		intron	N/A	ENSP00000400359.1	Q9UJ98-1

Frequencies

GnomAD3 genomes AF: 0.000943 AC: 129 AN: 136820 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000401

Gnomad AMI AF: 0.00230

Gnomad AMR AF: 0.000743

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.000421

Gnomad SAS AF: 0.00140

Gnomad FIN AF: 0.00334

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000950

Gnomad OTH AF: 0.00271

GnomAD4 exome AF: 0.0526 AC: 4381 AN: 83320 Hom.: 0 Cov.: 0 AF XY: 0.0533 AC XY: 2416 AN XY: 45362

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

African (AFR) AF: 0.0434 AC: 84 AN: 1934

American (AMR) AF: 0.0477 AC: 146 AN: 3064

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 118 AN: 2076

East Asian (EAS) AF: 0.0380 AC: 183 AN: 4810

South Asian (SAS) AF: 0.0545 AC: 613 AN: 11256

European-Finnish (FIN) AF: 0.0461 AC: 237 AN: 5142

Middle Eastern (MID) AF: 0.0551 AC: 15 AN: 272

European-Non Finnish (NFE) AF: 0.0543 AC: 2707 AN: 49888

Other (OTH) AF: 0.0570 AC: 278 AN: 4878

⚠️ 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: 0.000943 AC: 129 AN: 136822 Hom.: 1 Cov.: 27 AF XY: 0.00108 AC XY: 71 AN XY: 65592

African (AFR) AF: 0.000427 AC: 16 AN: 37432

American (AMR) AF: 0.000743 AC: 10 AN: 13466

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 4 AN: 3286

East Asian (EAS) AF: 0.000423 AC: 2 AN: 4732

South Asian (SAS) AF: 0.00117 AC: 5 AN: 4274

European-Finnish (FIN) AF: 0.00334 AC: 25 AN: 7486

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

European-Non Finnish (NFE) AF: 0.000950 AC: 60 AN: 63170

Other (OTH) AF: 0.00269 AC: 5 AN: 1856

Alfa AF: 0.000234 Hom.: 77

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.053
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35965210; hg19: chr7-99778503;