12-48065129-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001267594.2(SENP1):c.1211A>G(p.Gln404Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,609,310 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (14 hom.)
• Consequence: SENP1 NM_001267594.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.710

Genes affected

SENP1 (HGNC:17927): (SUMO specific peptidase 1) This gene encodes a cysteine protease that specifically targets members of the small ubiquitin-like modifier (SUMO) protein family. This protease regulates SUMO pathways by deconjugating sumoylated proteins. This protease also functions to process the precursor SUMO proteins into their mature form. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070144236).
• BP6: Variant 12-48065129-T-C is Benign according to our data. Variant chr12-48065129-T-C is described in ClinVar as [Benign]. Clinvar id is 779947.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000834 (127/152350) while in subpopulation EAS AF= 0.0198 (103/5190). AF 95% confidence interval is 0.0167. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SENP1	NM_001267594.2	c.1211A>G	p.Gln404Arg	missense_variant	12/18	ENST00000549518.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SENP1	ENST00000549518.6	c.1211A>G	p.Gln404Arg	missense_variant	12/18	1	NM_001267594.2	P4

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0198

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00150 AC: 372 AN: 248284 Hom.: 4 AF XY: 0.00131 AC XY: 176 AN XY: 134708

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0193

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.000492 AC: 717 AN: 1456960 Hom.: 14 Cov.: 28 AF XY: 0.000415 AC XY: 301 AN XY: 725224

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0119

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.00362

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74502

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0198

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.00109

ExAC AF: 0.00126 AC: 152

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.063	T;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.73	D
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	D;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.87	N;N;N
REVEL	Benign	0.024
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.20
MVP		0.60
ClinPred		0.0058	T
GERP RS		1.4
Varity_R		0.055
gMVP		0.21

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: rs182987633; hg19: chr12-48458912;