19-507526-G-T

Variant names:

• chr19-507526-G-T
• rs1978652022
• NM_033513.3:c.20G>T

Variant summary

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

The NM_033513.3(TPGS1):​c.20G>T​(p.Arg7Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000079 in 1,265,926 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: TPGS1 NM_033513.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.74
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033513.3. 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
	TPGS1	NM_033513.3	MANE Select	c.20G>T	p.Arg7Leu	missense	Exon 1 of 2	NP_277048.2	Q6ZTW0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPGS1	ENST00000359315.6	TSL:1 MANE Select	c.20G>T	p.Arg7Leu	missense	Exon 1 of 2	ENSP00000352265.4	Q6ZTW0-1
	TPGS1	ENST00000588278.1	TSL:6	n.27G>T		non_coding_transcript_exon	Exon 1 of 1
	MADCAM1-AS1	ENST00000592413.2	TSL:5	n.308C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.90e-7 AC: 1 AN: 1265926 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 616586

African (AFR) AF: 0.00 AC: 0 AN: 25688

American (AMR) AF: 0.0000545 AC: 1 AN: 18352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18258

East Asian (EAS) AF: 0.00 AC: 0 AN: 30116

South Asian (SAS) AF: 0.00 AC: 0 AN: 61596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5008

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1013736

Other (OTH) AF: 0.00 AC: 0 AN: 51448

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.41		Gain of ubiquitination at K6 (P = 0.0267)
MVP		0.57
MPC		2.2
ClinPred		1.0	D
GERP RS		4.0
PromoterAI		0.043	Neutral
Varity_R		0.61
gMVP		0.58
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs1978652022; hg19: chr19-507526;