chr6-54343319-T-C

Position:

• chr6-54343319-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014464.4(TINAG):​c.718T>C​(p.Cys240Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000708 in 1,413,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TINAG NM_014464.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

Genes affected

TINAG (HGNC:14599): (tubulointerstitial nephritis antigen) This gene encodes a glycoprotein that is restricted within the kidney to the basement membranes underlying the epithelium of Bowman's capsule and proximal and distal tubules. Autoantibodies against this protein are found in sera of patients with tubulointerstital nephritis, membranous nephropathy and anti-glomerular basement membrane nephritis. Ontogeny studies suggest that the expression of this antigen is developmentally regulated in a precise spatial and temporal pattern throughout nephrogenesis. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TINAG	NM_014464.4	c.718T>C	p.Cys240Arg	missense_variant	5/11	ENST00000259782.9	NP_055279.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TINAG	ENST00000259782.9	c.718T>C	p.Cys240Arg	missense_variant	5/11	1	NM_014464.4	ENSP00000259782.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413254 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 701736

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: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 13, 2023

The c.718T>C (p.C240R) alteration is located in exon 5 (coding exon 5) of the TINAG gene. This alteration results from a T to C substitution at nucleotide position 718, causing the cysteine (C) at amino acid position 240 to be replaced by an arginine (R). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.98		Gain of disorder (P = 0.0138);
MVP		0.78
MPC		0.049
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.95

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-54208117;