chr3-20174605-T-C

Variant names:

• chr3-20174605-T-C
• rs142110258
• NM_001199251.3:c.926A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001199251.3(SGO1):​c.926A>G​(p.Tyr309Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,601,064 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (3 hom.)
• Consequence: SGO1 NM_001199251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0860
• Publications: 0 publications found

Genes affected

SGO1 (HGNC:25088): (shugoshin 1) The protein encoded by this gene is a member of the shugoshin family of proteins. This protein is thought to protect centromeric cohesin from cleavage during mitotic prophase by preventing phosphorylation of a cohesin subunit. Reduced expression of this gene leads to the premature loss of centromeric cohesion, mis-segregation of sister chromatids, and mitotic arrest. Evidence suggests that this protein also protects a small subset of cohesin found along the length of the chromosome arms during mitotic prophase. An isoform lacking exon 6 has been shown to play a role in the cohesion of centrioles (PMID: 16582621 and PMID:18331714). Mutations in this gene have been associated with Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome, characterized by the co-occurrence of Sick Sinus Syndrome (SSS) and Chronic Intestinal Pseudo-obstruction (CIPO) within the first four decades of life (PMID:25282101). Fibroblast cells from CAID patients exhibited both increased cell proliferation and higher rates of senescence. Pseudogenes of this gene have been found on chromosomes 1 and 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

SGO1-AS1 (HGNC:41081): (SGO1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042305887).
• BP6: Variant 3-20174605-T-C is Benign according to our data. Variant chr3-20174605-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 787255.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199251.3. 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
	SGO1	NM_001199251.3	MANE Select	c.926A>G	p.Tyr309Cys	missense	Exon 6 of 8	NP_001186180.1	Q5FBB7-6
	SGO1	NM_001012410.5		c.926A>G	p.Tyr309Cys	missense	Exon 6 of 9	NP_001012410.1	Q5FBB7-1
	SGO1	NM_001199252.3		c.926A>G	p.Tyr309Cys	missense	Exon 6 of 9	NP_001186181.1	Q5FBB7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGO1	ENST00000412997.6	TSL:1 MANE Select	c.926A>G	p.Tyr309Cys	missense	Exon 6 of 8	ENSP00000410458.1	Q5FBB7-6
	SGO1	ENST00000263753.8	TSL:1	c.926A>G	p.Tyr309Cys	missense	Exon 6 of 9	ENSP00000263753.4	Q5FBB7-1
	SGO1	ENST00000421451.5	TSL:1	c.926A>G	p.Tyr309Cys	missense	Exon 6 of 9	ENSP00000414129.1	Q5FBB7-1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000394 AC: 91 AN: 230950 AF XY: 0.000312

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000976

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000172 AC: 249 AN: 1448724 Hom.: 3 Cov.: 31 AF XY: 0.000133 AC XY: 96 AN XY: 720040

African (AFR) AF: 0.00674 AC: 219 AN: 32504

American (AMR) AF: 0.000142 AC: 6 AN: 42236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53040

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107056

Other (OTH) AF: 0.000318 AC: 19 AN: 59798

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74502

African (AFR) AF: 0.00512 AC: 213 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000607 Hom.: 1

Bravo AF: 0.00194

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000504 AC: 61

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.4
DANN	Benign	0.32
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.086
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.012
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.0030	B
Vest4		0.038
MVP		0.092
MPC		0.022
ClinPred		0.0033	T
GERP RS		-0.88
Varity_R		0.039
gMVP		0.044
Mutation Taster		=94/6	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: rs142110258; hg19: chr3-20216097;