rs770176902

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-26735457-G-A
• chr4-26735457-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018317.4(TBC1D19):​c.1087G>A​(p.Val363Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000464 in 1,529,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TBC1D19 NM_018317.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3621703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4	c.1087G>A	p.Val363Ile	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>A	p.Val363Ile	missense_variant, splice_region_variant	Exon 16 of 21	1	NM_018317.4	ENSP00000264866.4
TBC1D19	ENST00000511789.5	c.892G>A	p.Val298Ile	missense_variant, splice_region_variant	Exon 13 of 18	1		ENSP00000425569.1
TBC1D19	ENST00000502873.5	n.1197G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 20	1

Frequencies

GnomAD3 genomes AF: 0.0000274 AC: 4 AN: 146002 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000252

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000451

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000445 AC: 8 AN: 179600 AF XY: 0.0000519

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000526

Gnomad NFE exome AF: 0.0000661

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000484 AC: 67 AN: 1383264 Hom.: 0 Cov.: 30 AF XY: 0.0000540 AC XY: 37 AN XY: 685508

African (AFR) AF: 0.0000332 AC: 1 AN: 30144

American (AMR) AF: 0.0000286 AC: 1 AN: 34914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24612

East Asian (EAS) AF: 0.00 AC: 0 AN: 37472

South Asian (SAS) AF: 0.00 AC: 0 AN: 76056

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5164

European-Non Finnish (NFE) AF: 0.0000581 AC: 62 AN: 1067444

Other (OTH) AF: 0.0000352 AC: 2 AN: 56862

GnomAD4 genome AF: 0.0000274 AC: 4 AN: 146002 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 70700

African (AFR) AF: 0.0000252 AC: 1 AN: 39720

American (AMR) AF: 0.00 AC: 0 AN: 14668

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4996

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8868

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

European-Non Finnish (NFE) AF: 0.0000451 AC: 3 AN: 66518

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.0000948 Hom.: 0

ExAC AF: 0.0000251 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1087G>A (p.V363I) alteration is located in exon 16 (coding exon 16) of the TBC1D19 gene. This alteration results from a G to A substitution at nucleotide position 1087, causing the valine (V) at amino acid position 363 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		8.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.15
Sift	Benign	0.16	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.84	P;.
Vest4		0.63
MutPred		0.45		Loss of catalytic residue at V363 (P = 0.0062);.;
MVP		0.44
MPC		0.32
ClinPred		0.12	T
GERP RS		5.7
Varity_R		0.14
gMVP		0.49
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		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;