8-55773658-C-A

Variant names:

• chr8-55773658-C-A
• rs749831575
• NM_024831.8:c.40C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024831.8(TGS1):​c.40C>A​(p.Leu14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. L14F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TGS1 NM_024831.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 5 publications found

Genes affected

TGS1 (HGNC:17843): (trimethylguanosine synthase 1) Enables RNA trimethylguanosine synthase activity. Involved in 7-methylguanosine cap hypermethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.24223101).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024831.8. 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
	TGS1	NM_024831.8	MANE Select	c.40C>A	p.Leu14Ile	missense	Exon 1 of 13	NP_079107.6
	TGS1	NM_001363184.2		c.-175C>A		5_prime_UTR	Exon 1 of 12	NP_001350113.1
	TGS1	NM_001317902.2		c.-175C>A		5_prime_UTR	Exon 1 of 11	NP_001304831.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGS1	ENST00000260129.6	TSL:1 MANE Select	c.40C>A	p.Leu14Ile	missense	Exon 1 of 13	ENSP00000260129.5	Q96RS0
	TGS1	ENST00000523948.5	TSL:1	n.40C>A		non_coding_transcript_exon	Exon 1 of 11	ENSP00000430467.1	E5RJW7
	TGS1	ENST00000938743.1		c.40C>A	p.Leu14Ile	missense	Exon 1 of 13	ENSP00000608802.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247584 AF XY: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459032 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725780

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

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.00 AC: 0 AN: 85636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110958

Other (OTH) AF: 0.00 AC: 0 AN: 60272

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.066
Sift	Uncertain	0.025	D
Sift4G	Benign	0.10	T
Polyphen		0.91	P
Vest4		0.35
MutPred		0.23		Gain of helix (P = 0.0696)
MVP		0.49
MPC		0.089
ClinPred		0.89	D
GERP RS		4.1
PromoterAI		-0.0047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.099
gMVP		0.28
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs749831575; hg19: chr8-56686217;