rs237025

Variant names:

• chr6-149400554-G-A
• rs237025
• NM_001002255.2:c.163G>A
• SUMO4 p.Val55Met

Your query was ambiguous. Multiple possible variants found:

• chr6-149400554-G-A
• chr6-149400554-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -10 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Moderate

The NM_001002255.2(SUMO4):c.163G>A (p.Val55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.513 (AC=828,175) in the gnomAD database across 1,613,990 control chromosomes, including 216,559 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.721. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.57 (25727 hom., cov: 33)
  • Exomes 𝑓: 0.51 (190832 hom.)
• Consequence: SUMO4 NM_001002255.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:5
• Conservation: PhyloP100: 0.259
• Publications: 145 publications found

Genes affected

SUMO4 (HGNC:21181): (small ubiquitin like modifier 4) This gene is a member of the SUMO gene family. This family of genes encode small ubiquitin-related modifiers that are attached to proteins and control the target proteins' subcellular localization, stability, or activity. The protein described in this record is located in the cytoplasm and specifically modifies IKBA, leading to negative regulation of NF-kappa-B-dependent transcription of the IL12B gene. A specific polymorphism in this SUMO gene, which leads to the M55V substitution, has been associated with type I diabetes. The RefSeq contains this polymorphism. [provided by RefSeq, Jul 2008]

SUMO4 Gene-Disease associations (from GenCC):

• type 1 diabetes mellitus 5

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

TAB2 (HGNC:17075): (TGF-beta activated kinase 1 (MAP3K7) binding protein 2) The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for for the IL-1 induced activation of nuclear factor kappaB and MAPK8/JNK. This protein forms a kinase complex with TRAF6, MAP3K7 and TAB1, and it thus serves as an adaptor that links MAP3K7 and TRAF6. This protein, along with TAB1 and MAP3K7, also participates in the signal transduction induced by TNFSF11/RANKl through the activation of the receptor activator of NF-kappaB (TNFRSF11A/RANK), which may regulate the development and function of osteoclasts. Studies of the related mouse protein indicate that it functions to protect against liver damage caused by chemical stressors. Mutations in this gene cause congenital heart defects, multiple types, 2 (CHTD2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

TAB2 Gene-Disease associations (from GenCC):

• chromosome 6q24-q25 deletion syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• congenital heart defects, multiple types, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Illumina, Laboratory for Molecular Medicine
• polyvalvular heart disease syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7213 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001002255.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMO4	NM_001002255.2	MANE Select	c.163G>A	p.Val55Met	missense	Exon 1 of 1	NP_001002255.1	Q6EEV6
	TAB2	NM_001292034.3	MANE Select	c.1939+1370G>A		intron	N/A	NP_001278963.1	Q9NYJ8-1
	TAB2	NM_001369506.1		c.1939+1370G>A		intron	N/A	NP_001356435.1	Q9NYJ8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUMO4	ENST00000326669.6	TSL:6 MANE Select	c.163G>A	p.Val55Met	missense	Exon 1 of 1	ENSP00000318635.4	Q6EEV6
	TAB2	ENST00000637181.2	TSL:1 MANE Select	c.1939+1370G>A		intron	N/A	ENSP00000490618.1	Q9NYJ8-1
	TAB2	ENST00000470466.5	TSL:1	n.*538+1370G>A		intron	N/A	ENSP00000432709.1	Q9NYJ8-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.572	AC:86908	Hom:25691	AN:152006	Cov:33
GnomAD2 exomes	AF: 0.554	AC:139242	Hom:	AN:251486	Cov:
GnomAD4 exome	AF: 0.507	AC:741165	Hom:190832	AN:1461864	Cov:70
GnomAD4 genome	AF: 0.572	AC:87010	Hom:25727	AN:152126	Cov:33
TOPMed (Bravo)	AF: 0.584	AC:154498	Hom:46637	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.522	AC:166853	Hom:44676	AN:319760	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.528	AC:1236	Hom:331	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.711	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.510	AC:151	Hom:	AN:296	Cov:
ESP6500 (Exome Variant Server)	AF: 0.562	AC:7308	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.717	AC:2491	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.680	AC:4918	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.482	AC:968	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.684	AC:84001	Hom:28764	AN:122814	Cov:
Turkish Variome	AF: 0.481	AC:3231	Hom:785	AN:6724	Cov:
UK10K	AF: 0.490	AC:3702	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.707	AC:6337	Hom:2227	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.532 *	5907	11112	0.524 *	9225	17616
BipEx(Bipolar disorder (including schizoaffective))	0.492	13976	28420	0.491	14159	28844
Epi25(Epilepsy)	0.530	22223	41958	0.522	34883	66888
SCHEMA(Schizophrenia)	0.588	96632	164316	0.580	158145	272560

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	1	Type 1 diabetes mellitus 5 (3)
-	-	2	not specified (2)
-	-	1	Diabetes mellitus type 1 (1)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	10
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.070
DANN	Benign	0.31
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.11	N
FuncVEP CTI	Benign	0.028
GPN-Star LLR	N/A	-1.2
GPN-Star score	N/A	1.2
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	92/8	disease causing (ClinVar)
PhyloP100	Benign	0.26
popEVE	Benign	-2.0
PrimateAI	Benign	0.35	T
PromoterAI	N/A	-0.0074	Neutral
PROVEAN	Benign	2.5	N
REVEL	Benign	0.079
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
VESM-3B	Benign	-4.1

Showing 24 of 24 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.030	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs237025;

hg19: chr6-149721690;

COSMIC: COSV53852721;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar