chr17-17848835-C-T

Variant names:

• chr17-17848835-C-T
• NM_001082968.2:c.1363G>A

Variant summary

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

The NM_001082968.2(TOM1L2):​c.1363G>A​(p.Val455Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 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: 6.8e-7 (0 hom.)
• Consequence: TOM1L2 NM_001082968.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21
• Publications: 0 publications found

Genes affected

TOM1L2 (HGNC:11984): (target of myb1 like 2 membrane trafficking protein) This gene belongs to a small gene family whose members have an N-terminal VHS domain followed by a GAT domain; domains which typically participate in vesicular trafficking. The canonical protein encoded by this gene also has a C-terminal clathrin binding motif. This protein has been shown to interact with Tollip, clathrin and ubiquitin and is thought to play a role in endosomal sorting. This gene resides in the 3.7 Mb deletion of chromosome region 17p11.2 that is associated with Smith-Magenis syndrome. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Apr 2017]

ENSG00000301763 (HGNC:):

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=0.32706523).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082968.2. 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
	TOM1L2	NM_001082968.2	MANE Select	c.1363G>A	p.Val455Ile	missense	Exon 14 of 15	NP_001076437.1	Q6ZVM7-1
	TOM1L2	NM_001350332.2		c.1450G>A	p.Val484Ile	missense	Exon 15 of 16	NP_001337261.1
	TOM1L2	NM_001350333.2		c.1303G>A	p.Val435Ile	missense	Exon 13 of 14	NP_001337262.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOM1L2	ENST00000379504.8	TSL:2 MANE Select	c.1363G>A	p.Val455Ile	missense	Exon 14 of 15	ENSP00000368818.3	Q6ZVM7-1
	TOM1L2	ENST00000581396.6	TSL:1	c.1213G>A	p.Val405Ile	missense	Exon 13 of 14	ENSP00000464297.1	Q6ZVM7-2
	TOM1L2	ENST00000890541.1		c.1618G>A	p.Val540Ile	missense	Exon 16 of 17	ENSP00000560600.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727218

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

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	0.18
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.18
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.14		Loss of phosphorylation at T456 (P = 0.2132)
MVP		0.59
MPC		0.55
ClinPred		0.89	D
GERP RS		4.6
Varity_R		0.10
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr17-17752149;