17-79940936-T-C

Position:

• chr17-79940936-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019020.4(TBC1D16):​c.2227A>G​(p.Met743Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,445,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TBC1D16 NM_019020.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.61

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023059756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D16	NM_019020.4	c.2227A>G	p.Met743Val	missense_variant	12/12	ENST00000310924.7	NP_061893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D16	ENST00000310924.7	c.2227A>G	p.Met743Val	missense_variant	12/12	1	NM_019020.4	ENSP00000309794.2
TBC1D16	ENST00000340848.11	c.1141A>G	p.Met381Val	missense_variant	8/8	1		ENSP00000341517.7
TBC1D16	ENST00000576768.5	c.1102A>G	p.Met368Val	missense_variant	8/8	1		ENSP00000461522.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1445078 Hom.: 0 Cov.: 32 AF XY: 0.0000126 AC XY: 9 AN XY: 716834

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

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: 0.0000127

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Feb 06, 2023

The c.2227A>G (p.M743V) alteration is located in exon 12 (coding exon 11) of the TBC1D16 gene. This alteration results from a A to G substitution at nucleotide position 2227, causing the methionine (M) at amino acid position 743 to be replaced by a valine (V). 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	0.077
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.016
DANN	Benign	0.55
DEOGEN2	Benign	0.0079	T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.35	T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.69	N;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.22	N;.;N
REVEL	Benign	0.012
Sift	Benign	0.33	T;.;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.015
MutPred		0.12		Gain of catalytic residue at M743 (P = 0.0806);.;.;
MVP		0.17
MPC		0.049
ClinPred		0.10	T
GERP RS		-6.2
Varity_R		0.020
gMVP		0.15

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: rs1718893598; hg19: chr17-77914735;