Genetic Variant NM_001040284.3:c.4C>G (chr16-50152956-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040284.3(TENT4B):c.4C>G(p.Arg2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000133 in 1,506,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. R2W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 28)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

TENT4B
NM_001040284.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.36

Publications

3 publications found

Variant links:

Genes affected

TENT4B (HGNC:30758): (terminal nucleotidyltransferase 4B) Enables guanylyltransferase activity and polynucleotide adenylyltransferase activity. Involved in several processes, including RNA metabolic process; negative regulation of telomere maintenance via telomerase; and regulation of mRNA stability. Located in cytoplasm and nucleolus. Part of TRAMP complex. [provided by Alliance of Genome Resources, Apr 2022]

TENT4B links:

ENSG00000260381 (HGNC:):

ENSG00000260381 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11349344).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040284.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TENT4B	NM_001040284.3	c.4C>G	p.Arg2Gly	missense	Exon 1 of 13	NP_001035374.2	Q8NDF8-5
TENT4B	NM_001040285.3	c.4C>G	p.Arg2Gly	missense	Exon 1 of 13	NP_001035375.2
TENT4B	NM_001365323.2	c.-110C>G		5_prime_UTR	Exon 1 of 13	NP_001352252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENT4B	ENST00000436909.8	TSL:2	c.4C>G	p.Arg2Gly	missense	Exon 1 of 13	ENSP00000396995.3	Q8NDF8-5
	ENSG00000260381	ENST00000832509.1		n.104G>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.00000668

AC:

AN:

149590

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000915

AC:

AN:

109314

AF XY:

0.00

show subpopulations

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:

0.0000242

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1356660

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28912

American (AMR)

AF:

0.00

AC:

AN:

33474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24270

East Asian (EAS)

AF:

0.00

AC:

AN:

32678

South Asian (SAS)

AF:

0.00

AC:

AN:

76676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5020

European-Non Finnish (NFE)

AF:

9.38e-7

AC:

AN:

1065792

Other (OTH)

AF:

0.00

AC:

AN:

56500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000668

AC:

AN:

149590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72986

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

40790

American (AMR)

AF:

0.00

AC:

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

4954

South Asian (SAS)

AF:

0.00

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10046

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67300

Other (OTH)

AF:

0.00

AC:

AN:

2062

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.9

(source)

DANN

Benign

0.52

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.22

M_CAP

Benign

0.051

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

-1.4

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.37

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Sift4G

Benign

0.086

Vest4

0.14

MutPred

0.30

Loss of methylation at R2 (P = 0.0204)

MVP

0.093

MPC

1.5

ClinPred

0.14

GERP RS

-0.79

PromoterAI

0.069

Neutral

(source)

gMVP

0.34

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over