SUMO4 p.Val55Leu

Variant names:

• chr6-149400554-G-C
• NM_001002255.2:c.163G>C
• SUMO4 p.Val55Leu

Your query was ambiguous. Multiple possible variants found:

• chr6-149400554-G-C
• chr6-149400554-G-T
• chr6-149400554-GTG-CTA
• chr6-149400554-GTG-CTC
• chr6-149400554-GTG-CTT
• chr6-149400554-GTG-TTA

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_001002255.2(SUMO4):c.163G>C (p.Val55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V55M: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 2062)

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUMO4 NM_001002255.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• Publications: 0 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: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	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).

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>C p.Val55Leu	missense	Exon 1 of 1	Prot: NP_001002255.1 UniProt:
	TAB2 NM_001292034.3	MANE Select	c.1939+1370G>C	intron	Intron 6 of 6	Prot: NP_001278963.1 UniProt:
	TAB2 NM_001369506.1		c.1939+1370G>C	intron	Intron 7 of 7	Prot: NP_001356435.1 UniProt:

SUMO4 NM_001002255.2

MANE Select

HGVSc / HGVSpc.163G>Cp.Val55Leu

Exon rankExon 1 of 1

missense

Prot: NP_001002255.1UniProt: Q6EEV6

TAB2 NM_001292034.3

MANE Select

HGVSc / HGVSpc.1939+1370G>C

Exon rankIntron 6 of 6

intron

Prot: NP_001278963.1UniProt: Q9NYJ8-1

TAB2 NM_001369506.1

HGVSc / HGVSpc.1939+1370G>C

Exon rankIntron 7 of 7

intron

Prot: NP_001356435.1UniProt: Q9NYJ8-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SUMO4 ENST00000326669.6	TSL:6MANE Select	c.163G>C p.Val55Leu	missense	Exon 1 of 1	Prot: ENSP00000318635.4 UniProt:
	TAB2 ENST00000637181.2	TSL:1MANE Select	c.1939+1370G>C	intron	Intron 6 of 6	Prot: ENSP00000490618.1 UniProt:
	TAB2 ENST00000470466.5	TSL:1	n.*538+1370G>C	intron	Intron 7 of 7	Prot: ENSP00000432709.1 UniProt:

SUMO4 ENST00000326669.6

TSL:6MANE Select

HGVSc / HGVSpc.163G>Cp.Val55Leu

Exon rankExon 1 of 1

missense

Prot: ENSP00000318635.4UniProt: Q6EEV6

TAB2 ENST00000637181.2

TSL:1MANE Select

HGVSc / HGVSpc.1939+1370G>C

Exon rankIntron 6 of 6

intron

Prot: ENSP00000490618.1UniProt: Q9NYJ8-1

TAB2 ENST00000470466.5

TSL:1

HGVSc / HGVSpn.*538+1370G>C

Exon rankIntron 7 of 7

intron

Prot: ENSP00000432709.1UniProt: 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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:70
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	9.2
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.1
DANN	Benign	0.41
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.59	D
FuncVEP CTI	Benign	0.25
GPN-Star LLR	N/A	-1.8
GPN-Star score	N/A	1.8
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.97	T
Mutation Taster	N/A	94/6	polymorphism
PhyloP100	Benign	0.26
popEVE	Benign	-2.1
PrimateAI	Benign	0.35	T
PromoterAI	N/A	0.0016	Neutral
PROVEAN	Benign	0.50	N
REVEL	Benign	0.050
Sift	Benign	0.20	T
Sift4G	Benign	0.56	T
VESM-3B	Benign	-4.7

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.040	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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr6-149721690;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar