6-137880103-A-C

Variant names:

• chr6-137880103-A-C
• rs142253225
• NM_001270508.2:c.1939A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001270508.2(TNFAIP3):​c.1939A>C​(p.Thr647Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T647T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: TNFAIP3 NM_001270508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4 O:1
• Conservation: PhyloP100: -0.431
• Publications: 34 publications found

Genes affected

TNFAIP3 (HGNC:11896): (TNF alpha induced protein 3) This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2012]

TNFAIP3 Gene-Disease associations (from GenCC):

• autoinflammatory syndrome, familial, Behcet-like 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary pediatric Behçet-like disease

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287393 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005445957).
• BP6: Variant 6-137880103-A-C is Benign according to our data. Variant chr6-137880103-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135345.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00193 (294/152288) while in subpopulation AMR AF = 0.00497 (76/15286). AF 95% confidence interval is 0.00407. There are 0 homozygotes in GnomAd4. There are 146 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 294 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270508.2. 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
	TNFAIP3	NM_001270508.2	MANE Select	c.1939A>C	p.Thr647Pro	missense	Exon 8 of 9	NP_001257437.1
	TNFAIP3	NM_001270507.2		c.1939A>C	p.Thr647Pro	missense	Exon 8 of 9	NP_001257436.1
	TNFAIP3	NM_006290.4		c.1939A>C	p.Thr647Pro	missense	Exon 8 of 9	NP_006281.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFAIP3	ENST00000612899.5	TSL:5 MANE Select	c.1939A>C	p.Thr647Pro	missense	Exon 8 of 9	ENSP00000481570.1
	TNFAIP3	ENST00000237289.8	TSL:1	c.1939A>C	p.Thr647Pro	missense	Exon 8 of 9	ENSP00000237289.4
	TNFAIP3	ENST00000420009.6	TSL:3	c.1939A>C	p.Thr647Pro	missense	Exon 8 of 9	ENSP00000401562.2

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152170 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00221

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00188 AC: 474 AN: 251476 AF XY: 0.00196

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00200 AC: 2923 AN: 1461894 Hom.: 2 Cov.: 31 AF XY: 0.00204 AC XY: 1482 AN XY: 727248

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00282 AC: 126 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00608 AC: 159 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.000684 AC: 59 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00209 AC: 2329 AN: 1112012

Other (OTH) AF: 0.00235 AC: 142 AN: 60396

GnomAD4 genome AF: 0.00193 AC: 294 AN: 152288 Hom.: 0 Cov.: 33 AF XY: 0.00196 AC XY: 146 AN XY: 74468

African (AFR) AF: 0.000601 AC: 25 AN: 41564

American (AMR) AF: 0.00497 AC: 76 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00221 AC: 150 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00217 Hom.: 2

Bravo AF: 0.00213

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00188 AC: 228

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Autoinflammatory syndrome, familial, Behcet-like (1)
-	1	-	Autoinflammatory syndrome, familial, Behcet-like 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.9
DANN	Benign	0.96
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.43
Sift4G	Benign	0.16	T
Vest4		0.35
MVP		0.37
ClinPred		0.0027	T
GERP RS		-2.6
Varity_R		0.092
Mutation Taster		=29/71	disease causing

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: rs142253225; hg19: chr6-138201240; COSMIC: COSV99396292; COSMIC: COSV99396292;