Genetic Variant TLCD3B:p.Arg217Leu (chr16-30025358-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_031478.6(TLCD3B):c.650G>T(p.Arg217Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,476 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. R217H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TLCD3B
NM_031478.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.20

Publications

0 publications found

Variant links:

Genes affected

TLCD3B (HGNC:25295): (TLC domain containing 3B) This gene encodes a transmembrane protein, which may be a likely target of peroxisome proliferator-activated receptor gamma (PPAR-gamma). The product of the orthologous gene in mouse is related to obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

TLCD3B links:

C16orf92 (HGNC:26346): (chromosome 16 open reading frame 92) Predicted to be involved in fusion of sperm to egg plasma membrane involved in single fertilization. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

C16orf92 links:

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ACMG classification

Classification was made for transcript

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_031478.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLCD3B	NM_031478.6	MANE Select	c.650G>T	p.Arg217Leu	missense	Exon 5 of 5	NP_113666.2	Q71RH2-1
TLCD3B	NM_001352173.2		c.908G>T	p.Arg303Leu	missense	Exon 6 of 6	NP_001339102.1
TLCD3B	NM_001318504.2		c.500G>T	p.Arg167Leu	missense	Exon 5 of 5	NP_001305433.1	Q71RH2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLCD3B	ENST00000380495.9	TSL:1 MANE Select	c.650G>T	p.Arg217Leu	missense	Exon 5 of 5	ENSP00000369863.4	Q71RH2-1
TLCD3B	ENST00000279389.8	TSL:1	c.500G>T	p.Arg167Leu	missense	Exon 5 of 5	ENSP00000279389.4	Q71RH2-2
TLCD3B	ENST00000934494.1		c.647G>T	p.Arg216Leu	missense	Exon 5 of 5	ENSP00000604553.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1444476

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32928

American (AMR)

AF:

0.00

AC:

AN:

43046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25844

East Asian (EAS)

AF:

0.00

AC:

AN:

38590

South Asian (SAS)

AF:

0.00

AC:

AN:

84230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51088

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103444

Other (OTH)

AF:

0.00

AC:

AN:

59560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.1

PhyloP100

3.2

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.40

Sift

Uncertain

0.022

Sift4G

Uncertain

0.025

Polyphen

0.011

Vest4

0.62

MutPred

0.58

Loss of methylation at R217 (P = 0.2437)

MVP

0.82

MPC

1.0

ClinPred

0.98

GERP RS

3.7

Varity_R

0.39

gMVP

0.54

Mutation Taster

=70/30

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over