Genetic Variant SUMO4:p.Val55Leu (chr6-149400554-GTG-CTT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_001002255.2(SUMO4):c.163_165delGTGinsCTT (p.Val55Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.55

Publications

0 publications found

Variant links:

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

SUMO4 links:

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

TAB2 links:

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new If you want to explore the variant's impact on the transcript NM_001002255.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

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.

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

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SUMO4 NM_001002255.2	MANE Select	c.163_165delGTGinsCTT p.Val55Leu	missense	N/A	Prot: NP_001002255.1 UniProt: Q6EEV6
TAB2 NM_001292034.3	MANE Select	c.1939+1370_1939+1372delGTGinsCTT	intron	Intron 6 of 6	Prot: NP_001278963.1 UniProt: Q9NYJ8-1
TAB2 NM_001369506.1		c.1939+1370_1939+1372delGTGinsCTT	intron	Intron 7 of 7	Prot: NP_001356435.1 UniProt: Q9NYJ8-1

SUMO4 NM_001002255.2

MANE Select

HGVSc / HGVSpc.163_165delGTGinsCTTp.Val55Leu

Exon rankN/A

missense

Prot: NP_001002255.1UniProt: Q6EEV6

TAB2 NM_001292034.3

MANE Select

HGVSc / HGVSpc.1939+1370_1939+1372delGTGinsCTT

Exon rankIntron 6 of 6

intron

Prot: NP_001278963.1UniProt: Q9NYJ8-1

TAB2 NM_001369506.1

HGVSc / HGVSpc.1939+1370_1939+1372delGTGinsCTT

Exon rankIntron 7 of 7

intron

Prot: NP_001356435.1UniProt: Q9NYJ8-1

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SUMO4 ENST00000326669.6	TSL:6MANE Select	c.163_165delGTGinsCTT p.Val55Leu	missense	N/A	Prot: ENSP00000318635.4 UniProt: Q6EEV6
TAB2 ENST00000637181.2	TSL:1MANE Select	c.1939+1370_1939+1372delGTGinsCTT	intron	Intron 6 of 6	Prot: ENSP00000490618.1 UniProt: Q9NYJ8-1
TAB2 ENST00000470466.5	TSL:1	n.538+1370_538+1372delGTGinsCTT	intron	Intron 7 of 7	Prot: ENSP00000432709.1 UniProt: Q9NYJ8-2

SUMO4 ENST00000326669.6

TSL:6MANE Select

HGVSc / HGVSpc.163_165delGTGinsCTTp.Val55Leu

Exon rankN/A

missense

Prot: ENSP00000318635.4UniProt: Q6EEV6

TAB2 ENST00000637181.2

TSL:1MANE Select

HGVSc / HGVSpc.1939+1370_1939+1372delGTGinsCTT

Exon rankIntron 6 of 6

intron

Prot: ENSP00000490618.1UniProt: Q9NYJ8-1

TAB2 ENST00000470466.5

TSL:1

HGVSc / HGVSpn.*538+1370_*538+1372delGTGinsCTT

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence