NM_001082968.2:c.1481G>A

Variant names:

• chr17-17847678-C-T
• rs371456416
• NM_001082968.2:c.1481G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001082968.2(TOM1L2):​c.1481G>A​(p.Arg494Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TOM1L2 NM_001082968.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06736714).

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.1481G>A	p.Arg494Gln	missense	Exon 15 of 15	NP_001076437.1	Q6ZVM7-1
	TOM1L2	NM_001350332.2		c.1568G>A	p.Arg523Gln	missense	Exon 16 of 16	NP_001337261.1
	TOM1L2	NM_001350333.2		c.1421G>A	p.Arg474Gln	missense	Exon 14 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.1481G>A	p.Arg494Gln	missense	Exon 15 of 15	ENSP00000368818.3	Q6ZVM7-1
	TOM1L2	ENST00000581396.6	TSL:1	c.1331G>A	p.Arg444Gln	missense	Exon 14 of 14	ENSP00000464297.1	Q6ZVM7-2
	TOM1L2	ENST00000890541.1		c.1736G>A	p.Arg579Gln	missense	Exon 17 of 17	ENSP00000560600.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.0000798 AC: 20 AN: 250498 AF XY: 0.0000738

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461550 Hom.: 0 Cov.: 34 AF XY: 0.0000454 AC XY: 33 AN XY: 727074

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111888

Other (OTH) AF: 0.000116 AC: 7 AN: 60380

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74466

African (AFR) AF: 0.000481 AC: 20 AN: 41560

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.0000775 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.8
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.061
Sift	Benign	0.24	T
Sift4G	Benign	0.23	T
Polyphen		0.98	D
Vest4		0.10
MVP		0.56
MPC		0.50
ClinPred		0.048	T
GERP RS		3.9
Varity_R		0.053
gMVP		0.21
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs371456416; hg19: chr17-17750992; COSMIC: COSV58889592;