chr6-149400554-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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 frequency of 0.513 in 1,613,990 control chromosomes in the GnomAD database, including 216,559 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.57 ( 25727 hom., cov: 33)

Exomes 𝑓: 0.51 ( 190832 hom. )

Consequence

SUMO4
NM_001002255.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:5

Conservation

PhyloP100: 0.259

Publications

145 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 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: Laboratory for Molecular Medicine, Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
polyvalvular heart disease syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TAB2 links:

Genome browser will be placed here

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.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.982837E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

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

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

GnomAD3 genomes

AF:

0.572

AC:

86908

AN:

152006

Hom.:

25691

Cov.:

show subpopulations

Gnomad AFR

AF:

0.718

Gnomad AMI

AF:

0.407

Gnomad AMR

AF:

0.563

Gnomad ASJ

AF:

0.467

Gnomad EAS

AF:

0.716

Gnomad SAS

AF:

0.588

Gnomad FIN

AF:

0.536

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.487

Gnomad OTH

AF:

0.555

GnomAD2 exomes

AF:

0.554

AC:

139242

AN:

251486

AF XY:

0.548

show subpopulations

Gnomad AFR exome

AF:

0.725

Gnomad AMR exome

AF:

0.616

Gnomad ASJ exome

AF:

0.477

Gnomad EAS exome

AF:

0.719

Gnomad FIN exome

AF:

0.531

Gnomad NFE exome

AF:

0.488

Gnomad OTH exome

AF:

0.532

GnomAD4 exome

AF:

0.507

AC:

741165

AN:

1461864

Hom.:

190832

Cov.:

AF XY:

0.508

AC XY:

369141

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.729

AC:

24402

AN:

33476

American (AMR)

AF:

0.614

AC:

27439

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.474

AC:

12387

AN:

26136

East Asian (EAS)

AF:

0.703

AC:

27906

AN:

39700

South Asian (SAS)

AF:

0.577

AC:

49800

AN:

86258

European-Finnish (FIN)

AF:

0.535

AC:

28587

AN:

53410

Middle Eastern (MID)

AF:

0.470

AC:

2709

AN:

5768

European-Non Finnish (NFE)

AF:

0.482

AC:

536500

AN:

1111996

Other (OTH)

AF:

0.520

AC:

31435

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

23691

47383

71074

94766

118457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16066

32132

48198

64264

80330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.572

AC:

87010

AN:

152126

Hom.:

25727

Cov.:

AF XY:

0.575

AC XY:

42742

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.718

AC:

29817

AN:

41510

American (AMR)

AF:

0.564

AC:

8617

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.467

AC:

1619

AN:

3468

East Asian (EAS)

AF:

0.715

AC:

3706

AN:

5180

South Asian (SAS)

AF:

0.588

AC:

2835

AN:

4820

European-Finnish (FIN)

AF:

0.536

AC:

5658

AN:

10562

Middle Eastern (MID)

AF:

0.425

AC:

125

AN:

294

European-Non Finnish (NFE)

AF:

0.487

AC:

33086

AN:

67994

Other (OTH)

AF:

0.560

AC:

1179

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1872

3744

5615

7487

9359

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

738

1476

2214

2952

3690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.516

Hom.:

39126

Bravo

AF:

0.584

Asia WGS

AF:

0.717

AC:

2491

AN:

3478

EpiCase

AF:

0.482

EpiControl

AF:

0.485

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Type 1 diabetes mellitus 5 (3)

not specified (2)

Diabetes mellitus type 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.070

(source)

DANN

Benign

0.31

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.11

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-0.97

PhyloP100

0.26

PrimateAI

Benign

0.35

PROVEAN

Benign

2.5

REVEL

Benign

0.079

Sift

Benign

1.0

Sift4G

Benign

1.0

PromoterAI

-0.0074

Neutral

(source)

gMVP

0.041

Mutation Taster

=92/8

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over