rs145021348

Variant names:

• chr4-2742502-C-G
• rs145021348
• NM_024309.4:c.1045G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-2742502-C-G
• chr4-2742502-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024309.4(TNIP2):​c.1045G>C​(p.Ala349Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,592,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TNIP2 NM_024309.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00400
• Publications: 1 publications found

Genes affected

TNIP2 (HGNC:19118): (TNFAIP3 interacting protein 2) This gene encodes a protein which acts as an inhibitor of NFkappaB activation. The encoded protein is also involved in MAP/ERK signaling pathway in specific cell types. It may be involved in apoptosis of endothelial cells. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on the X chromosome.[provided by RefSeq, May 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043698132).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024309.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIP2	NM_024309.4	MANE Select	c.1045G>C	p.Ala349Pro	missense	Exon 6 of 6	NP_077285.3
	TNIP2	NM_001292016.2		c.796G>C	p.Ala266Pro	missense	Exon 5 of 5	NP_001278945.1	D6RGJ2
	TNIP2	NM_001161527.2		c.724G>C	p.Ala242Pro	missense	Exon 6 of 6	NP_001154999.1	Q8NFZ5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIP2	ENST00000315423.12	TSL:1 MANE Select	c.1045G>C	p.Ala349Pro	missense	Exon 6 of 6	ENSP00000321203.7	Q8NFZ5-1
	TNIP2	ENST00000892917.1		c.1057G>C	p.Ala353Pro	missense	Exon 6 of 6	ENSP00000562976.1
	TNIP2	ENST00000892919.1		c.1036G>C	p.Ala346Pro	missense	Exon 6 of 6	ENSP00000562978.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000834 AC: 2 AN: 239748 AF XY: 0.00000771

Gnomad AFR exome AF: 0.0000635

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439984 Hom.: 0 Cov.: 34 AF XY: 0.00000280 AC XY: 2 AN XY: 713500

⚠️ 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: 32806

American (AMR) AF: 0.00 AC: 0 AN: 42918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 38720

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097736

Other (OTH) AF: 0.00 AC: 0 AN: 59354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.2
DANN	Benign	0.63
DEOGEN2	Benign	0.086	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.40	N
PhyloP100		0.0040
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.014
Sift	Benign	0.32	T
Sift4G	Benign	0.22	T
Polyphen		0.0010	B
Vest4		0.035
MVP		0.23
MPC		0.41
ClinPred		0.024	T
GERP RS		-2.2
Varity_R		0.047
gMVP		0.23
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs145021348; hg19: chr4-2744229;