chr8-144440024-C-T

Variant names:

• chr8-144440024-C-T
• rs2229315
• NM_013432.5:c.1477G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013432.5(TONSL):​c.1477G>A​(p.Gly493Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 1,224,910 control chromosomes in the GnomAD database, including 167,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22161 hom., cov: 34)
  • Exomes 𝑓: 0.52 (145584 hom.)
• Consequence: TONSL NM_013432.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.812
• Publications: 30 publications found

Genes affected

TONSL (HGNC:7801): (tonsoku like, DNA repair protein) The protein encoded by this gene is thought to be a negative regulator of NF-kappa-B mediated transcription. The encoded protein may bind NF-kappa-B complexes and trap them in the cytoplasm, preventing them from entering the nucleus and interacting with the DNA. Phosphorylation of this protein targets it for degradation by the ubiquitination pathway, which frees the NF-kappa-B complexes to enter the nucleus. [provided by RefSeq, Jul 2008]

TONSL-AS1 (HGNC:51556): (TONSL antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.515272E-6).
• BP6: Variant 8-144440024-C-T is Benign according to our data. Variant chr8-144440024-C-T is described in ClinVar as Benign. ClinVar VariationId is 1167022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013432.5. 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
	TONSL	NM_013432.5	MANE Select	c.1477G>A	p.Gly493Ser	missense	Exon 11 of 26	NP_038460.4
	TONSL-AS1	NR_109770.1		n.*131C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	ENST00000409379.8	TSL:1 MANE Select	c.1477G>A	p.Gly493Ser	missense	Exon 11 of 26	ENSP00000386239.3
	TONSL	ENST00000932056.1		c.1477G>A	p.Gly493Ser	missense	Exon 11 of 27	ENSP00000602115.1
	TONSL	ENST00000971177.1		c.1477G>A	p.Gly493Ser	missense	Exon 11 of 26	ENSP00000641236.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81685 AN: 152012 Hom.: 22144 Cov.: 34

Gnomad AFR AF: 0.587

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.639

Gnomad NFE AF: 0.530

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.503 AC: 121897 AN: 242106 AF XY: 0.503

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.465

Gnomad ASJ exome AF: 0.665

Gnomad EAS exome AF: 0.371

Gnomad FIN exome AF: 0.517

Gnomad NFE exome AF: 0.530

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.517 AC: 554447 AN: 1072780 Hom.: 145584 Cov.: 15 AF XY: 0.514 AC XY: 283214 AN XY: 550800

African (AFR) AF: 0.589 AC: 15334 AN: 26028

American (AMR) AF: 0.472 AC: 20406 AN: 43206

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 15630 AN: 23648

East Asian (EAS) AF: 0.395 AC: 15042 AN: 38040

South Asian (SAS) AF: 0.424 AC: 33270 AN: 78394

European-Finnish (FIN) AF: 0.516 AC: 26773 AN: 51848

Middle Eastern (MID) AF: 0.636 AC: 3168 AN: 4978

European-Non Finnish (NFE) AF: 0.526 AC: 399420 AN: 759062

Other (OTH) AF: 0.534 AC: 25404 AN: 47576

GnomAD4 genome AF: 0.537 AC: 81752 AN: 152130 Hom.: 22161 Cov.: 34 AF XY: 0.535 AC XY: 39770 AN XY: 74358

African (AFR) AF: 0.587 AC: 24375 AN: 41514

American (AMR) AF: 0.508 AC: 7761 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2312 AN: 3464

East Asian (EAS) AF: 0.390 AC: 2018 AN: 5168

South Asian (SAS) AF: 0.409 AC: 1974 AN: 4822

European-Finnish (FIN) AF: 0.520 AC: 5508 AN: 10596

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.530 AC: 36059 AN: 67972

Other (OTH) AF: 0.529 AC: 1115 AN: 2106

Alfa AF: 0.532 Hom.: 42851

Bravo AF: 0.540

TwinsUK AF: 0.517 AC: 1918

ALSPAC AF: 0.511 AC: 1968

ESP6500AA AF: 0.578 AC: 2541

ESP6500EA AF: 0.535 AC: 4593

ExAC AF: 0.502 AC: 60677

Asia WGS AF: 0.423 AC: 1474 AN: 3478

EpiCase AF: 0.534

EpiControl AF: 0.536

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Sponastrime dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.74
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0000095	T
PhyloP100		0.81
Sift4G	Benign	0.31	T
Vest4		0.032
ClinPred		0.0033	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
Mutation Taster		=96/4	polymorphism (auto)

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: rs2229315; hg19: chr8-145665407; COSMIC: COSV68048177; COSMIC: COSV68048177;