17-17869344-C-A

Variant names:

• chr17-17869344-C-A
• rs547369838
• NM_001082968.2:c.907G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001082968.2(TOM1L2):​c.907G>T​(p.Glu303*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TOM1L2 NM_001082968.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.83
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.907G>T	p.Glu303*	stop_gained	Exon 8 of 15	NP_001076437.1	Q6ZVM7-1
	TOM1L2	NM_001350332.2		c.907G>T	p.Glu303*	stop_gained	Exon 8 of 16	NP_001337261.1
	TOM1L2	NM_001350333.2		c.907G>T	p.Glu303*	stop_gained	Exon 8 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.907G>T	p.Glu303*	stop_gained	Exon 8 of 15	ENSP00000368818.3	Q6ZVM7-1
	TOM1L2	ENST00000581396.6	TSL:1	c.757G>T	p.Glu253*	stop_gained	Exon 7 of 14	ENSP00000464297.1	Q6ZVM7-2
	TOM1L2	ENST00000890541.1		c.907G>T	p.Glu303*	stop_gained	Exon 8 of 17	ENSP00000560600.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459220 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726004

⚠️ 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: 33470

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: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51062

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		7.8
Vest4		0.41
GERP RS		5.7

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: rs547369838; hg19: chr17-17772658;