chr4-26735457-G-T

Variant names:

• chr4-26735457-G-T
• rs770176902
• NM_018317.4:c.1087G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_018317.4(TBC1D19):​c.1087G>T​(p.Val363Phe) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. V363I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBC1D19 NM_018317.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.08
• Publications: 0 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4	c.1087G>T	p.Val363Phe	missense_variant, splice_region_variant	Exon 16 of 21	ENST00000264866.9	NP_060787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D19	ENST00000264866.9	c.1087G>T	p.Val363Phe	missense_variant, splice_region_variant	Exon 16 of 21	1	NM_018317.4	ENSP00000264866.4
TBC1D19	ENST00000511789.5	c.892G>T	p.Val298Phe	missense_variant, splice_region_variant	Exon 13 of 18	1		ENSP00000425569.1
TBC1D19	ENST00000502873.5	n.1197G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 20	1

Frequencies

GnomAD3 genomes AF: 0.000123 AC: 18 AN: 145834 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00102

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000903

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000228 AC: 41 AN: 179600 AF XY: 0.000228

Gnomad AFR exome AF: 0.0000847

Gnomad AMR exome AF: 0.000197

Gnomad ASJ exome AF: 0.000116

Gnomad EAS exome AF: 0.000507

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000118 AC: 163 AN: 1382714 Hom.: 0 Cov.: 30 AF XY: 0.000108 AC XY: 74 AN XY: 685254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000266 AC: 8 AN: 30106

American (AMR) AF: 0.00308 AC: 107 AN: 34762

Ashkenazi Jewish (ASJ) AF: 0.0000814 AC: 2 AN: 24584

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37474

South Asian (SAS) AF: 0.000184 AC: 14 AN: 75998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5154

European-Non Finnish (NFE) AF: 0.0000253 AC: 27 AN: 1067230

Other (OTH) AF: 0.0000704 AC: 4 AN: 56820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000123 AC: 18 AN: 145834 Hom.: 0 Cov.: 28 AF XY: 0.000127 AC XY: 9 AN XY: 70618

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000756 AC: 3 AN: 39686

American (AMR) AF: 0.00 AC: 0 AN: 14666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 4994

South Asian (SAS) AF: 0.00 AC: 0 AN: 4612

European-Finnish (FIN) AF: 0.00102 AC: 9 AN: 8822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000903 AC: 6 AN: 66436

Other (OTH) AF: 0.00 AC: 0 AN: 2004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00180 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M;.
PhyloP100		8.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.47
Sift	Benign	0.088	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.99	D;.
Vest4		0.93
MutPred		0.43		Loss of sheet (P = 0.0315);.;
MVP		0.59
MPC		0.94
ClinPred		0.088	T
GERP RS		5.7
Varity_R		0.58
gMVP		0.91
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -2

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

Other links and lift over

dbSNP: rs770176902; hg19: chr4-26737079;