chr8-55786346-G-A

Variant names:

• chr8-55786346-G-A
• rs61740025
• NM_024831.8:c.448G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024831.8(TGS1):​c.448G>A​(p.Asp150Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00706 in 1,612,404 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (57 hom.)
• Consequence: TGS1 NM_024831.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.06
• Publications: 11 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028980374).
• BP6: Variant 8-55786346-G-A is Benign according to our data. Variant chr8-55786346-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 782749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 gene

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.448G>A	p.Asp150Asn	missense	Exon 4 of 13	NP_079107.6
	TGS1	NM_001363184.2		c.169G>A	p.Asp57Asn	missense	Exon 3 of 12	NP_001350113.1
	TGS1	NM_001317902.2		c.169G>A	p.Asp57Asn	missense	Exon 3 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.448G>A	p.Asp150Asn	missense	Exon 4 of 13	ENSP00000260129.5	Q96RS0
	TGS1	ENST00000523948.5	TSL:1	n.*221G>A		non_coding_transcript_exon	Exon 3 of 11	ENSP00000430467.1	E5RJW7
	TGS1	ENST00000523948.5	TSL:1	n.*221G>A		3_prime_UTR	Exon 3 of 11	ENSP00000430467.1	E5RJW7

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 741 AN: 152144 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00892

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00525 AC: 1312 AN: 249990 AF XY: 0.00536

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00913

Gnomad OTH exome AF: 0.00707

GnomAD4 exome AF: 0.00729 AC: 10640 AN: 1460142 Hom.: 57 Cov.: 31 AF XY: 0.00727 AC XY: 5281 AN XY: 726258

African (AFR) AF: 0.00123 AC: 41 AN: 33436

American (AMR) AF: 0.00153 AC: 68 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39676

South Asian (SAS) AF: 0.00273 AC: 234 AN: 85626

European-Finnish (FIN) AF: 0.00219 AC: 117 AN: 53394

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5764

European-Non Finnish (NFE) AF: 0.00862 AC: 9577 AN: 1111206

Other (OTH) AF: 0.00699 AC: 422 AN: 60334

GnomAD4 genome AF: 0.00486 AC: 740 AN: 152262 Hom.: 5 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74448

African (AFR) AF: 0.00128 AC: 53 AN: 41556

American (AMR) AF: 0.00183 AC: 28 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00893 AC: 607 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00764 Hom.: 9

Bravo AF: 0.00494

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00568 AC: 689

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00971

EpiControl AF: 0.00794

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.085
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.15	B
Vest4		0.10
MVP		0.50
MPC		0.055
ClinPred		0.0065	T
GERP RS		4.9
Varity_R		0.036
gMVP		0.11
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: rs61740025; hg19: chr8-56698905; COSMIC: COSV99036156; COSMIC: COSV99036156;