chr6-149400554-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25727 hom., cov: 33)
  • Exomes 𝑓: 0.51 (190832 hom.)
• Consequence: SUMO4 NM_001002255.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 0.259

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]

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.982837E-7).
• BP6: Variant 6-149400554-G-A is Benign according to our data. Variant chr6-149400554-G-A is described in ClinVar as [Benign]. Clinvar id is 2062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-149400554-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUMO4	NM_001002255.2	c.163G>A	p.Val55Met	missense_variant	Exon 1 of 1	ENST00000326669.6	NP_001002255.1
TAB2	NM_001292034.3	c.1939+1370G>A		intron_variant	Intron 6 of 6	ENST00000637181.2	NP_001278963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUMO4	ENST00000326669.6	c.163G>A	p.Val55Met	missense_variant	Exon 1 of 1	6	NM_001002255.2	ENSP00000318635.4
TAB2	ENST00000637181.2	c.1939+1370G>A		intron_variant	Intron 6 of 6	1	NM_001292034.3	ENSP00000490618.1

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86908 AN: 152006 Hom.: 25691 Cov.: 33

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

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.: 70 AF XY: 0.508 AC XY: 369141 AN XY: 727240

Gnomad4 AFR exome AF: 0.729 AC: 24402 AN: 33476

Gnomad4 AMR exome AF: 0.614 AC: 27439 AN: 44724

Gnomad4 ASJ exome AF: 0.474 AC: 12387 AN: 26136

Gnomad4 EAS exome AF: 0.703 AC: 27906 AN: 39700

Gnomad4 SAS exome AF: 0.577 AC: 49800 AN: 86258

Gnomad4 FIN exome AF: 0.535 AC: 28587 AN: 53410

Gnomad4 NFE exome AF: 0.482 AC: 536500 AN: 1111996

Gnomad4 Remaining exome AF: 0.520 AC: 31435 AN: 60396

GnomAD4 genome AF: 0.572 AC: 87010 AN: 152126 Hom.: 25727 Cov.: 33 AF XY: 0.575 AC XY: 42742 AN XY: 74374

Gnomad4 AFR AF: 0.718 AC: 0.718309 AN: 0.718309

Gnomad4 AMR AF: 0.564 AC: 0.563645 AN: 0.563645

Gnomad4 ASJ AF: 0.467 AC: 0.46684 AN: 0.46684

Gnomad4 EAS AF: 0.715 AC: 0.715444 AN: 0.715444

Gnomad4 SAS AF: 0.588 AC: 0.588174 AN: 0.588174

Gnomad4 FIN AF: 0.536 AC: 0.535694 AN: 0.535694

Gnomad4 NFE AF: 0.487 AC: 0.486602 AN: 0.486602

Gnomad4 OTH AF: 0.560 AC: 0.559829 AN: 0.559829

Alfa AF: 0.516 Hom.: 39126

Bravo AF: 0.584

TwinsUK AF: 0.496 AC: 1841

ALSPAC AF: 0.483 AC: 1861

ESP6500AA AF: 0.711 AC: 3134

ESP6500EA AF: 0.485 AC: 4174

ExAC AF: 0.555 AC: 67383

Asia WGS AF: 0.717 AC: 2491 AN: 3478

EpiCase AF: 0.482

EpiControl AF: 0.485

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Type 1 diabetes mellitus 5 Pathogenic:1 Benign:1

Feb 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25189908, 15247916, 21158221, 19915388, 20518843, 22884980, 19410319, 17130563) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.5	N
REVEL	Benign	0.079
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.036
MPC		0.057
ClinPred		0.0067	T
GERP RS		-0.47
gMVP		0.041
Mutation Taster		=92/8	disease causing (ClinVar)

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

Publications

LitVar

Other links and lift over

dbSNP: rs237025; hg19: chr6-149721690; COSMIC: COSV53852721;