Genetic Variant TPD52L3:p.Ser120Tyr (chr9-6328954-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001001874.3(TPD52L3):c.359C>A(p.Ser120Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

TPD52L3
NM_001001874.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.04

Variant links:

Genes affected

TPD52L3 (HGNC:23382): (TPD52 like 3) This gene encodes a member of the tumor protein D52-like family of proteins. These proteins are characterized by an N-terminal coiled-coil motif that is used to form homo- and heteromeric complexes with other tumor protein D52-like proteins. The encoded protein may play a role in spermatogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

TPD52L3 links:

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ACMG classification

Classification made for transcript

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
TPD52L3	NM_001001874.3 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 2	ENST00000314556.4	NP_001001874.2	Q96J77-2A0A140VKH0
TPD52L3	NM_033516.6 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 1		NP_277051.4	Q96J77-1
TPD52L3	NM_001001875.4 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 2		NP_001001875.2	Q96J77-3
TPD52L3	XM_017015280.3 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 3		XP_016870769.1	Q96J77-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TPD52L3	ENST00000314556.4 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 2	1	NM_001001874.3	ENSP00000318665.3	Q96J77-2
TPD52L3	ENST00000381428.1 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 2	1		ENSP00000370836.1	Q96J77-3
TPD52L3	ENST00000344545.6 link	c.359C>A	p.Ser120Tyr	missense_variant	Exon 1 of 1	6		ENSP00000341677.5	Q96J77-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250350

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000955

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.359C>A (p.S120Y) alteration is located in exon 1 (coding exon 1) of the TPD52L3 gene. This alteration results from a C to A substitution at nucleotide position 359, causing the serine (S) at amino acid position 120 to be replaced by a tyrosine (Y). 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

Benign

0.18

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.025

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-0.47

MutationAssessor

Pathogenic

3.5

H;H;H

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.49

MutPred

0.77

Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);

MVP

0.26

MPC

0.035

ClinPred

0.63

GERP RS

3.7

Varity_R

0.97

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over