rs1046668

Positions:

• chr2-151370056-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000243347.5(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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.18 (2880 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15218 hom.)
• Consequence: TNFAIP6 ENST00000243347.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11

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]

LOC101929319 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFAIP6	NM_007115.4	c.431A>G	p.Gln144Arg	missense_variant	4/6	ENST00000243347.5	NP_009046.2
LOC101929319	NR_110248.1	n.306+2739T>C		intron_variant, non_coding_transcript_variant
TNFAIP6	XM_047445635.1	c.431A>G	p.Gln144Arg	missense_variant	4/6		XP_047301591.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFAIP6	ENST00000243347.5	c.431A>G	p.Gln144Arg	missense_variant	4/6	1	NM_007115.4	ENSP00000243347	P1
TNFAIP6	ENST00000460812.1	n.113A>G		non_coding_transcript_exon_variant	2/3	3

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

GnomAD3 exomes AF: 0.146 AC: 36744 AN: 251282 Hom.: 2997 AF XY: 0.142 AC XY: 19338 AN XY: 135842

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 SAS exome AF: 0.111

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

Gnomad4 AFR exome AF: 0.299

Gnomad4 AMR exome AF: 0.0970

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.145

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

Gnomad4 AFR AF: 0.290

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.159

Alfa AF: 0.148 Hom.: 4557

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 v4.3

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
MutationTaster	Benign	1.0	P
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

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

Other links and lift over

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