19-507651-C-T

Variant names:

• chr19-507651-C-T
• rs769086372
• NM_033513.3:c.145C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033513.3(TPGS1):​c.145C>T​(p.Arg49Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 1,234,968 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: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TPGS1 NM_033513.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

TPGS1 (HGNC:25058): (tubulin polyglutamylase complex subunit 1) Predicted to enable microtubule binding activity. Predicted to be involved in protein polyglutamylation. Predicted to act upstream of or within several processes, including adult behavior; chemical synaptic transmission; and sperm axoneme assembly. Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

MADCAM1-AS1 (HGNC:55315): (MADCAM1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPGS1	NM_033513.3	c.145C>T	p.Arg49Cys	missense_variant	Exon 1 of 2	ENST00000359315.6	NP_277048.2
MADCAM1-AS1	XR_007067073.1	n.239G>A		non_coding_transcript_exon_variant	Exon 1 of 2
MADCAM1-AS1	XR_936221.4	n.239G>A		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPGS1	ENST00000359315.6	c.145C>T	p.Arg49Cys	missense_variant	Exon 1 of 2	1	NM_033513.3	ENSP00000352265.4
TPGS1	ENST00000588278.1	n.152C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
MADCAM1-AS1	ENST00000592413.2	n.183G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000891 AC: 11 AN: 1234968 Hom.: 0 Cov.: 31 AF XY: 0.0000133 AC XY: 8 AN XY: 600874

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000323

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000403

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000868 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145C>T (p.R49C) alteration is located in exon 1 (coding exon 1) of the TPGS1 gene. This alteration results from a C to T substitution at nucleotide position 145, causing the arginine (R) at amino acid position 49 to be replaced by a cysteine (C). 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	0.54
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.16	T
Polyphen		0.93	P
Vest4		0.65
MutPred		0.46		Gain of catalytic residue at M47 (P = 2e-04);
MVP		0.91
MPC		2.0
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs769086372; hg19: chr19-507651;