chr19-507808-C-T

Variant names:

• chr19-507808-C-T
• rs775351801
• NM_033513.3:c.302C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_033513.3(TPGS1):​c.302C>T​(p.Ala101Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 1,211,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: TPGS1 NM_033513.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPGS1	NM_033513.3	c.302C>T	p.Ala101Val	missense_variant	Exon 1 of 2	ENST00000359315.6	NP_277048.2
MADCAM1-AS1	XR_007067073.1	n.82G>A		non_coding_transcript_exon_variant	Exon 1 of 2
MADCAM1-AS1	XR_936221.4	n.82G>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.302C>T	p.Ala101Val	missense_variant	Exon 1 of 2	1	NM_033513.3	ENSP00000352265.4
TPGS1	ENST00000588278.1	n.309C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
MADCAM1-AS1	ENST00000592413.2	n.26G>A		non_coding_transcript_exon_variant	Exon 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000330 AC: 4 AN: 1211464 Hom.: 0 Cov.: 31 AF XY: 0.00000510 AC XY: 3 AN XY: 588370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000726

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000332

Gnomad4 NFE exome AF: 0.00000101

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000287 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.302C>T (p.A101V) 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 302, causing the alanine (A) at amino acid position 101 to be replaced by a valine (V). 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	0.83
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.53		Gain of MoRF binding (P = 0.1275);
MVP		0.53
MPC		1.4
ClinPred		0.58	D
GERP RS		4.3
Varity_R		0.76
gMVP		0.49

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: rs775351801; hg19: chr19-507808;