8-55785875-C-T

Variant names:

• chr8-55785875-C-T
• rs370476485
• NM_024831.8:c.323C>T

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.323C>T​(p.Ala108Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. A108T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TGS1 NM_024831.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.840
• Publications: 0 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=0.0885852).

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.323C>T	p.Ala108Val	missense	Exon 3 of 13	NP_079107.6
	TGS1	NM_001363184.2		c.44C>T	p.Ala15Val	missense	Exon 2 of 12	NP_001350113.1
	TGS1	NM_001317902.2		c.44C>T	p.Ala15Val	missense	Exon 2 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.323C>T	p.Ala108Val	missense	Exon 3 of 13	ENSP00000260129.5	Q96RS0
	TGS1	ENST00000523948.5	TSL:1	n.*96C>T		non_coding_transcript_exon	Exon 2 of 11	ENSP00000430467.1	E5RJW7
	TGS1	ENST00000523948.5	TSL:1	n.*96C>T		3_prime_UTR	Exon 2 of 11	ENSP00000430467.1	E5RJW7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447220 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 719548

African (AFR) AF: 0.00 AC: 0 AN: 32652

American (AMR) AF: 0.0000247 AC: 1 AN: 40428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25460

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00 AC: 0 AN: 82740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107552

Other (OTH) AF: 0.00 AC: 0 AN: 59844

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.84
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.048
Sift	Benign	0.31	T
Sift4G	Benign	0.47	T
Polyphen		0.0060	B
Vest4		0.13
MutPred		0.24		Gain of sheet (P = 0.0344)
MVP		0.45
MPC		0.022
ClinPred		0.15	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.046
gMVP		0.16
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs370476485; hg19: chr8-56698434;