chr4-140622785-C-G

Variant names:

• chr4-140622785-C-G
• rs777508117
• NM_015130.3:c.3211G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015130.3(TBC1D9):​c.3211G>C​(p.Val1071Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,744 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. 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. V1071M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TBC1D9 NM_015130.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.119
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044187486).

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.3211G>C	p.Val1071Leu	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.3211G>C	p.Val1071Leu	missense	Exon 21 of 21	ENSP00000411197.2	Q6ZT07
	TBC1D9	ENST00000970329.1		c.3223G>C	p.Val1075Leu	missense	Exon 21 of 21	ENSP00000640388.1
	TBC1D9	ENST00000855917.1		c.3208G>C	p.Val1070Leu	missense	Exon 21 of 21	ENSP00000525976.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450744 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 721932

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111164

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.38
DANN	Benign	0.63
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.12
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.068
Sift	Benign	0.62	T
Sift4G	Benign	0.66	T
Polyphen		0.0	B
Vest4		0.029
MutPred		0.32		Gain of helix (P = 0.005)
MVP		0.23
MPC		0.48
ClinPred		0.022	T
GERP RS		-6.7
Varity_R		0.024
gMVP		0.098
Mutation Taster		=100/0	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: rs777508117; hg19: chr4-141543939;