19-47143522-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP4_Strong BP6_Moderate BS2

The NM_005500.3(SAE1):c.127G>A(p.Gly43Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,613,986 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (12 hom.)
• Consequence: SAE1 NM_005500.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.46

Genes affected

SAE1 (HGNC:30660): (SUMO1 activating enzyme subunit 1) Posttranslational modification of proteins by the addition of the small protein SUMO (see SUMO1; MIM 601912), or sumoylation, regulates protein structure and intracellular localization. SAE1 and UBA2 (MIM 613295) form a heterodimer that functions as a SUMO-activating enzyme for the sumoylation of proteins (Okuma et al., 1999 [PubMed 9920803]).[supplied by OMIM, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.044219077).
• BP6: Variant 19-47143522-G-A is Benign according to our data. Variant chr19-47143522-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2650142.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAE1	NM_005500.3	c.127G>A	p.Gly43Ser	missense_variant	2/9	ENST00000270225.12
SAE1	NM_001145713.2	c.127G>A	p.Gly43Ser	missense_variant	2/7
SAE1	NM_001145714.2	c.127G>A	p.Gly43Ser	missense_variant	2/8
SAE1	NR_027280.2	n.307G>A		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAE1	ENST00000270225.12	c.127G>A	p.Gly43Ser	missense_variant	2/9	1	NM_005500.3	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152024 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00685

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00109 AC: 274 AN: 251484 Hom.: 4 AF XY: 0.00141 AC XY: 192 AN XY: 135918

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00807

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000559 AC: 817 AN: 1461844 Hom.: 12 Cov.: 30 AF XY: 0.000782 AC XY: 569 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00780

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152142 Hom.: 2 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00685

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000907

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

SAE1: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.044	T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;.;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0090	D;.;.;D;D
Sift4G	Uncertain	0.056	T;.;D;D;T
Polyphen		1.0	.;.;.;D;.
Vest4		0.98
MutPred		0.82		Gain of MoRF binding (P = 0.1186);.;Gain of MoRF binding (P = 0.1186);Gain of MoRF binding (P = 0.1186);Gain of MoRF binding (P = 0.1186);
MVP		0.97
MPC		0.72
ClinPred		0.12	T
GERP RS		5.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.95
gMVP		0.79

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: rs199801330; hg19: chr19-47646779; COSMIC: COSV99538031;