17-79945004-C-A

Position:

• chr17-79945004-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019020.4(TBC1D16):​c.1812G>T​(p.Met604Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,424,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TBC1D16 NM_019020.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

Genes affected

TBC1D16 (HGNC:28356): (TBC1 domain family member 16) Enables GTPase activator activity. Involved in regulation of receptor recycling. Located in cytosol and early endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32890642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D16	NM_019020.4	c.1812G>T	p.Met604Ile	missense_variant	10/12	ENST00000310924.7	NP_061893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D16	ENST00000310924.7	c.1812G>T	p.Met604Ile	missense_variant	10/12	1	NM_019020.4	ENSP00000309794	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424246 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 704610

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.1812G>T (p.M604I) alteration is located in exon 10 (coding exon 9) of the TBC1D16 gene. This alteration results from a G to T substitution at nucleotide position 1812, causing the methionine (M) at amino acid position 604 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	Pathogenic	0.56
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T;.;.;.;T
Eigen	Benign	0.049
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.79	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.71	N;.;N;.;.
REVEL	Benign	0.087
Sift	Uncertain	0.012	D;.;D;.;.
Sift4G	Uncertain	0.017	D;D;D;D;D
Polyphen		0.47	P;.;.;.;.
Vest4		0.34
MutPred		0.62		Loss of disorder (P = 0.3647);.;.;.;.;
MVP		0.33
MPC		0.77
ClinPred		0.65	D
GERP RS		4.1
Varity_R		0.35
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs2032390185; hg19: chr17-77918803;