6-149400590-A-G

Position:

chr6-149400590-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001002255.2(SUMO4):c.199A>G(p.Ile67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,614,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

SUMO4
NM_001002255.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27

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 links:

TAB2 (HGNC:):

TAB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025373578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUMO4	NM_001002255.2 linkuse as main transcript	c.199A>G	p.Ile67Val	missense_variant	1/1	ENST00000326669.6	NP_001002255.1	Q6EEV6
TAB2	NM_001292034.3 linkuse as main transcript	c.1939+1406A>G		intron_variant		ENST00000637181.2	NP_001278963.1	Q9NYJ8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUMO4	ENST00000326669.6 linkuse as main transcript	c.199A>G	p.Ile67Val	missense_variant	1/1	6	NM_001002255.2	ENSP00000318635.4		Q6EEV6
TAB2	ENST00000637181.2 linkuse as main transcript	c.1939+1406A>G		intron_variant		1	NM_001292034.3	ENSP00000490618.1		Q9NYJ8-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000318

AC:

AN:

251488

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000229

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000189

AC:

276

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

133

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000519

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000590

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00248

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.000295

Hom.:

Bravo

AF:

0.000604

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The c.199A>G (p.I67V) alteration is located in exon 1 (coding exon 1) of the SUMO4 gene. This alteration results from a A to G substitution at nucleotide position 199, causing the isoleucine (I) at amino acid position 67 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.38

CADD

Benign

9.7

DANN

Benign

0.33

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Uncertain

0.81

M_CAP

Benign

0.0037

MetaRNN

Benign

0.025

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.90

REVEL

Benign

0.15

Sift

Benign

0.15

Sift4G

Benign

0.39

Vest4

0.30

MVP

0.30

MPC

0.054

ClinPred

0.072

GERP RS

-0.47

gMVP

0.032

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over