rs1046668

Variant names:

• chr2-151370056-A-G
• rs1046668
• NM_007115.4:c.431A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007115.4(TNFAIP6):​c.431A>G​(p.Gln144Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,302 control chromosomes in the GnomAD database, including 18,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2880 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15218 hom.)
• Consequence: TNFAIP6 NM_007115.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 40 publications found

Genes affected

TNFAIP6 (HGNC:11898): (TNF alpha induced protein 6) The protein encoded by this gene is a secretory protein that contains a hyaluronan-binding domain, and thus is a member of the hyaluronan-binding protein family. The hyaluronan-binding domain is known to be involved in extracellular matrix stability and cell migration. This protein has been shown to form a stable complex with inter-alpha-inhibitor (I alpha I), and thus enhance the serine protease inhibitory activity of I alpha I, which is important in the protease network associated with inflammation. This gene can be induced by proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-1. Enhanced levels of this protein are found in the synovial fluid of patients with osteoarthritis and rheumatoid arthritis.[provided by RefSeq, Dec 2010]

ENSG00000295625 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034234822).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007115.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP6	NM_007115.4	MANE Select	c.431A>G	p.Gln144Arg	missense	Exon 4 of 6	NP_009046.2
	LOC101929319	NR_110248.1		n.306+2739T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP6	ENST00000243347.5	TSL:1 MANE Select	c.431A>G	p.Gln144Arg	missense	Exon 4 of 6	ENSP00000243347.3
	TNFAIP6	ENST00000460812.1	TSL:3	n.113A>G		non_coding_transcript_exon	Exon 2 of 3
	ENSG00000295625	ENST00000731384.1		n.176+2739T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27552 AN: 151974 Hom.: 2871 Cov.: 32

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.146 AC: 36744 AN: 251282 AF XY: 0.142

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.0948

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.159

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.140 AC: 205048 AN: 1461210 Hom.: 15218 Cov.: 32 AF XY: 0.139 AC XY: 101183 AN XY: 726934

African (AFR) AF: 0.299 AC: 9991 AN: 33464

American (AMR) AF: 0.0970 AC: 4340 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3753 AN: 26116

East Asian (EAS) AF: 0.147 AC: 5829 AN: 39686

South Asian (SAS) AF: 0.110 AC: 9454 AN: 86238

European-Finnish (FIN) AF: 0.180 AC: 9622 AN: 53370

Middle Eastern (MID) AF: 0.0983 AC: 567 AN: 5766

European-Non Finnish (NFE) AF: 0.137 AC: 152716 AN: 1111478

Other (OTH) AF: 0.145 AC: 8776 AN: 60372

GnomAD4 genome AF: 0.181 AC: 27603 AN: 152092 Hom.: 2880 Cov.: 32 AF XY: 0.180 AC XY: 13410 AN XY: 74342

African (AFR) AF: 0.290 AC: 12033 AN: 41462

American (AMR) AF: 0.118 AC: 1800 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3468

East Asian (EAS) AF: 0.151 AC: 783 AN: 5172

South Asian (SAS) AF: 0.118 AC: 567 AN: 4822

European-Finnish (FIN) AF: 0.164 AC: 1728 AN: 10564

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9720 AN: 68008

Other (OTH) AF: 0.159 AC: 335 AN: 2112

Alfa AF: 0.153 Hom.: 8669

Bravo AF: 0.185

TwinsUK AF: 0.132 AC: 488

ALSPAC AF: 0.129 AC: 496

ESP6500AA AF: 0.295 AC: 1301

ESP6500EA AF: 0.138 AC: 1188

ExAC AF: 0.152 AC: 18424

Asia WGS AF: 0.139 AC: 484 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.0
DANN	Benign	0.52
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.056	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.85	L
PhyloP100		1.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.27
ClinPred		0.00042	T
GERP RS		3.5
Varity_R		0.18
gMVP		0.59
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1046668; hg19: chr2-152226570; COSMIC: COSV54639821; COSMIC: COSV54639821;