chr4-26659612-C-T

Variant names:

• chr4-26659612-C-T
• rs137972599
• NM_018317.4:c.496C>T

Variant summary

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

The NM_018317.4(TBC1D19):​c.496C>T​(p.Arg166Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000263 in 1,586,734 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R166H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: TBC1D19 NM_018317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75
• Publications: 4 publications found

Genes affected

TBC1D19 (HGNC:25624): (TBC1 domain family member 19) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018317.4. 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
	TBC1D19	NM_018317.4	MANE Select	c.496C>T	p.Arg166Cys	missense	Exon 8 of 21	NP_060787.2	Q8N5T2-1
	TBC1D19	NM_001292054.2		c.301C>T	p.Arg101Cys	missense	Exon 5 of 18	NP_001278983.1	Q8N5T2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D19	ENST00000264866.9	TSL:1 MANE Select	c.496C>T	p.Arg166Cys	missense	Exon 8 of 21	ENSP00000264866.4	Q8N5T2-1
	TBC1D19	ENST00000511789.5	TSL:1	c.301C>T	p.Arg101Cys	missense	Exon 5 of 18	ENSP00000425569.1	Q8N5T2-2
	TBC1D19	ENST00000502873.5	TSL:1	n.606C>T		non_coding_transcript_exon	Exon 8 of 20

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000417 AC: 104 AN: 249508 AF XY: 0.000408

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00828

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000263 AC: 378 AN: 1434632 Hom.: 1 Cov.: 29 AF XY: 0.000263 AC XY: 187 AN XY: 711894

African (AFR) AF: 0.000120 AC: 4 AN: 33218

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00847 AC: 215 AN: 25376

East Asian (EAS) AF: 0.0000510 AC: 2 AN: 39238

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82290

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52482

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5650

European-Non Finnish (NFE) AF: 0.000104 AC: 114 AN: 1092926

Other (OTH) AF: 0.000643 AC: 38 AN: 59108

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74298

African (AFR) AF: 0.000121 AC: 5 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000541 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000467 AC: 4

ExAC AF: 0.000354 AC: 43

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	0.32
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MVP		0.70
MPC		1.1
ClinPred		0.30	T
GERP RS		5.3
Varity_R		0.52
gMVP		0.62
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: -15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs137972599; hg19: chr4-26661234; COSMIC: COSV53514846;