chr4-140622575-G-C

Variant names:

• chr4-140622575-G-C
• rs1159096769
• NM_015130.3:c.3421C>G

Variant summary

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

The NM_015130.3(TBC1D9):​c.3421C>G​(p.Arg1141Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBC1D9 NM_015130.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14
• Publications: 1 publications found

Genes affected

TBC1D9 (HGNC:21710): (TBC1 domain family member 9) Predicted to enable GTPase activator activity. Predicted to be involved in activation of GTPase activity and intracellular protein transport. [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=0.07186183).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015130.3. 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
	TBC1D9	NM_015130.3	MANE Select	c.3421C>G	p.Arg1141Gly	missense	Exon 21 of 21	NP_055945.2	Q6ZT07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D9	ENST00000442267.3	TSL:1 MANE Select	c.3421C>G	p.Arg1141Gly	missense	Exon 21 of 21	ENSP00000411197.2	Q6ZT07
	TBC1D9	ENST00000970329.1		c.3433C>G	p.Arg1145Gly	missense	Exon 21 of 21	ENSP00000640388.1
	TBC1D9	ENST00000855917.1		c.3418C>G	p.Arg1140Gly	missense	Exon 21 of 21	ENSP00000525976.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248704 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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461630 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111850

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.074
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.64	N
PhyloP100		3.1
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.078
Sift	Benign	0.58	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.14		Loss of solvent accessibility (P = 0.0159)
MVP		0.24
MPC		0.79
ClinPred		0.14	T
GERP RS		4.0
Varity_R		0.096
gMVP		0.32
Mutation Taster		=91/9	polymorphism

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: rs1159096769; hg19: chr4-141543729;