6-125262835-C-G

Variant names:

• chr6-125262835-C-G
• rs199925644
• NM_003287.4:c.488C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003287.4(TPD52L1):​c.488C>G​(p.Thr163Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,458,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. T163M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TPD52L1 NM_003287.4 missense, splice_region
• Scores: Splicing: ADA: 0.9830
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.67
• Publications: 3 publications found

Genes affected

TPD52L1 (HGNC:12006): (TPD52 like 1) This gene encodes a member of a family of proteins that contain coiled-coil domains and may form hetero- or homomers. The encoded protein is involved in cell proliferation and calcium signaling. It also interacts with the mitogen-activated protein kinase kinase kinase 5 (MAP3K5/ASK1) and positively regulates MAP3K5-induced apoptosis. Multiple alternatively spliced transcript variants have been observed. [provided by RefSeq, Jan 2016]

HDDC2 (HGNC:21078): (HD domain containing 2) Predicted to enable 5'-deoxynucleotidase activity. Predicted to be involved in dephosphorylation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3623453).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003287.4. 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
	TPD52L1	NM_003287.4	MANE Select	c.488C>G	p.Thr163Arg	missense splice_region	Exon 7 of 7	NP_003278.1	Q16890-1
	TPD52L1	NM_001318903.2		c.503C>G	p.Thr168Arg	missense splice_region	Exon 8 of 8	NP_001305832.1	J3KNE7
	TPD52L1	NM_001300994.3		c.449C>G	p.Thr150Arg	missense splice_region	Exon 6 of 6	NP_001287923.1	E9PPQ1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPD52L1	ENST00000534000.6	TSL:1 MANE Select	c.488C>G	p.Thr163Arg	missense splice_region	Exon 7 of 7	ENSP00000434142.1	Q16890-1
	TPD52L1	ENST00000368402.9	TSL:1	c.427C>G	p.Arg143Gly	missense splice_region	Exon 6 of 6	ENSP00000357387.5	Q16890-2
	TPD52L1	ENST00000368388.6	TSL:1	c.388C>G	p.Arg130Gly	missense splice_region	Exon 5 of 5	ENSP00000357373.2	Q16890-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246442 AF XY: 0.00000751

Gnomad AFR exome AF: 0.00

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: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458024 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725138

African (AFR) AF: 0.00 AC: 0 AN: 33264

American (AMR) AF: 0.00 AC: 0 AN: 43606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25884

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110880

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.7
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.091
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.044	D
Polyphen		0.76	P
Vest4		0.30
MutPred		0.30		Loss of stability (P = 0.0044)
MVP		0.91
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.70
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.70
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

Other links and lift over

dbSNP: rs199925644; hg19: chr6-125583981;