2-161231000-A-T

Position:

• chr2-161231000-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BS2

The NM_001199135.3(TANK):​c.550A>T​(p.Thr184Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TANK NM_001199135.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

Genes affected

TANK (HGNC:11562): (TRAF family member associated NFKB activator) The TRAF (tumor necrosis factor receptor-associated factor) family of proteins associate with and transduce signals from members of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is found in the cytoplasm and can bind to TRAF1, TRAF2, or TRAF3, thereby inhibiting TRAF function by sequestering the TRAFs in a latent state in the cytoplasm. For example, the protein encoded by this gene can block TRAF2 binding to LMP1, the Epstein-Barr virus transforming protein, and inhibit LMP1-mediated NF-kappa-B activation. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

PSMD14-DT (HGNC:56104): (PSMD14 divergent transcript)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a mutagenesis_site Abolishes interaction with TRAF2 and TRAF3. (size 0) in uniprot entity TANK_HUMAN
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TANK	NM_001199135.3	c.550A>T	p.Thr184Ser	missense_variant	7/8	ENST00000392749.7	NP_001186064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TANK	ENST00000392749.7	c.550A>T	p.Thr184Ser	missense_variant	7/8	1	NM_001199135.3	ENSP00000376505.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 01, 2024

The c.550A>T (p.T184S) alteration is located in exon 7 (coding exon 6) of the TANK gene. This alteration results from a A to T substitution at nucleotide position 550, causing the threonine (T) at amino acid position 184 to be replaced by a serine (S). 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	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;T;D;D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.5	D;D;N;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.011	D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.75
MutPred		0.33		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);.;
MVP		0.62
MPC		0.94
ClinPred		0.93	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs199641620; hg19: chr2-162087511;