chr17-7627611-C-A

Variant names:

• chr17-7627611-C-A
• rs141081070
• NM_133491.5:c.25G>T

Variant summary

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

The NM_133491.5(SAT2):​c.25G>T​(p.Ala9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A9T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SAT2 NM_133491.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• Publications: 0 publications found

Genes affected

SAT2 (HGNC:23160): (spermidine/spermine N1-acetyltransferase family member 2) Enables diamine N-acetyltransferase activity and identical protein binding activity. Involved in polyamine metabolic process. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

SHBG (HGNC:10839): (sex hormone binding globulin) This gene encodes a steroid binding protein that was first described as a plasma protein secreted by the liver but is now thought to participate in the regulation of steroid responses. The encoded protein transports androgens and estrogens in the blood, binding each steroid molecule as a dimer formed from identical or nearly identical monomers. Polymorphisms in this gene have been associated with polycystic ovary syndrome and type 2 diabetes mellitus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133491.5. 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
	SAT2	NM_133491.5	MANE Select	c.25G>T	p.Ala9Ser	missense	Exon 1 of 6	NP_597998.1	Q96F10
	SAT2	NM_001320845.1		c.245G>T	p.Gly82Val	missense	Exon 1 of 6	NP_001307774.1	Q502X4
	SAT2	NM_001320846.1		c.245G>T	p.Gly82Val	missense	Exon 1 of 5	NP_001307775.1	Q96F10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAT2	ENST00000269298.10	TSL:1 MANE Select	c.25G>T	p.Ala9Ser	missense	Exon 1 of 6	ENSP00000269298.5	Q96F10
	SHBG	ENST00000575314.5	TSL:1	c.-61-2807C>A		intron	N/A	ENSP00000458559.1	I3L145
	SHBG	ENST00000572262.5	TSL:1	c.-61-2807C>A		intron	N/A	ENSP00000459999.1	I3L2X4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461070 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726832

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

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111648

Other (OTH) AF: 0.00 AC: 0 AN: 60356

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.021	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		2.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.56
MutPred		0.65		Gain of phosphorylation at A9 (P = 0.0174)
MVP		0.49
MPC		0.88
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.83
Mutation Taster		=63/37	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: rs141081070; hg19: chr17-7530929;