rs758508125

Variant names:

• chr5-151033634-G-A
• rs758508125
• NM_006058.5:c.1753C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006058.5(TNIP1):​c.1753C>T​(p.Leu585Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000016 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNIP1 NM_006058.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• Publications: 0 publications found

Genes affected

TNIP1 (HGNC:16903): (TNFAIP3 interacting protein 1) This gene encodes an A20-binding protein which plays a role in autoimmunity and tissue homeostasis through the regulation of nuclear factor kappa-B activation. Mutations in this gene have been associated with psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

TNIP1 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10574511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNIP1	NM_006058.5	c.1753C>T	p.Leu585Phe	missense_variant	Exon 16 of 18	ENST00000521591.6	NP_006049.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNIP1	ENST00000521591.6	c.1753C>T	p.Leu585Phe	missense_variant	Exon 16 of 18	1	NM_006058.5	ENSP00000430760.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000813 AC: 1 AN: 123074 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000164 AC: 2 AN: 1221238 Hom.: 0 Cov.: 33 AF XY: 0.00000169 AC XY: 1 AN XY: 591130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25898

American (AMR) AF: 0.0000489 AC: 1 AN: 20466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16640

East Asian (EAS) AF: 0.00 AC: 0 AN: 31714

South Asian (SAS) AF: 0.00 AC: 0 AN: 44584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4690

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 984118

Other (OTH) AF: 0.00 AC: 0 AN: 49272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000850 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1753C>T (p.L585F) alteration is located in exon 16 (coding exon 15) of the TNIP1 gene. This alteration results from a C to T substitution at nucleotide position 1753, causing the leucine (L) at amino acid position 585 to be replaced by a phenylalanine (F). 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	Benign	0.074
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;.;T;T;.
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.81	T;T;.;.;.;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	.;.;L;L;L;L;L
PhyloP100		1.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.70	N;N;N;N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.099	T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.77	.;.;P;.;P;P;.
Vest4		0.25
MutPred		0.17		.;Loss of catalytic residue at L585 (P = 0.0921);Loss of catalytic residue at L585 (P = 0.0921);Loss of catalytic residue at L585 (P = 0.0921);Loss of catalytic residue at L585 (P = 0.0921);Loss of catalytic residue at L585 (P = 0.0921);Loss of catalytic residue at L585 (P = 0.0921);
MVP		0.17
MPC		0.67
ClinPred		0.36	T
GERP RS		3.0
Varity_R		0.026
gMVP		0.15
Mutation Taster		=94/6	polymorphism

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: rs758508125; hg19: chr5-150413195;