6-125262882-C-T

Variant names:

• chr6-125262882-C-T
• rs368984698
• NM_003287.4:c.535C>T

Variant summary

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

The NM_003287.4(TPD52L1):​c.535C>T​(p.Leu179Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L179V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TPD52L1 NM_003287.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23
• Publications: 0 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=0.324234).

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.535C>T	p.Leu179Phe	missense	Exon 7 of 7	NP_003278.1	Q16890-1
	TPD52L1	NM_001318903.2		c.550C>T	p.Leu184Phe	missense	Exon 8 of 8	NP_001305832.1	J3KNE7
	TPD52L1	NM_001300994.3		c.496C>T	p.Leu166Phe	missense	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.535C>T	p.Leu179Phe	missense	Exon 7 of 7	ENSP00000434142.1	Q16890-1
	TPD52L1	ENST00000368402.9	TSL:1	c.*39C>T		3_prime_UTR	Exon 6 of 6	ENSP00000357387.5	Q16890-2
	TPD52L1	ENST00000368388.6	TSL:1	c.*39C>T		3_prime_UTR	Exon 5 of 5	ENSP00000357373.2	Q16890-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.038	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.56		Gain of glycosylation at S180 (P = 0.0805)
MVP		0.41
MPC		1.4
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.55
gMVP		0.56
Mutation Taster		=51/49	polymorphism

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: rs368984698; hg19: chr6-125584028;