17-54903757-G-A

Position:

• chr17-54903757-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005486.3(TOM1L1):​c.108G>A​(p.Met36Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TOM1L1 NM_005486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

Genes affected

TOM1L1 (HGNC:11983): (target of myb1 like 1 membrane trafficking protein) Enables clathrin binding activity and protein kinase binding activity. Involved in negative regulation of mitotic nuclear division; positive regulation of protein phosphorylation; and signal transduction. Located in cytosol and endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TOM1L1	NM_005486.3	c.108G>A	p.Met36Ile	missense_variant	2/16	ENST00000575882.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TOM1L1	ENST00000575882.6	c.108G>A	p.Met36Ile	missense_variant	2/16	1	NM_005486.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Nov 07, 2022

The c.108G>A (p.M36I) alteration is located in exon 2 (coding exon 2) of the TOM1L1 gene. This alteration results from a G to A substitution at nucleotide position 108, causing the methionine (M) at amino acid position 36 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;.;T;T;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;D;D;D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.38	T;T;T;D;T;T;D;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	.;.;D;.;.;.;.;.
REVEL	Benign	0.16
Sift	Uncertain	0.022	.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.020	D;D;D;D;D;D;D;D
Polyphen		0.46	.;P;.;.;.;.;.;.
Vest4		0.50
MutPred		0.57		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;.;
MVP		0.48
MPC		0.19
ClinPred		0.86	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2048364773; hg19: chr17-52981118;