Genetic Variant NM_005486.3:c.907G>T (chr17-54936701-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005486.3(TOM1L1):c.907G>T(p.Ala303Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,324 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: 6.9e-7 ( 0 hom. )

Consequence

TOM1L1
NM_005486.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.744

Variant links:

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]

TOM1L1 links:

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ACMG classification

Classification made for transcript

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=0.056741863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOM1L1	NM_005486.3 link	c.907G>T	p.Ala303Ser	missense_variant	Exon 9 of 16	ENST00000575882.6	NP_005477.2	O75674-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TOM1L1	ENST00000575882.6 link	c.907G>T	p.Ala303Ser	missense_variant	Exon 9 of 16	1	NM_005486.3	ENSP00000460823.1		O75674-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455324

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723928

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.907G>T (p.A303S) alteration is located in exon 9 (coding exon 9) of the TOM1L1 gene. This alteration results from a G to T substitution at nucleotide position 907, causing the alanine (A) at amino acid position 303 to be replaced by a serine (S). 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

0.076

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.023

.;T;.;.;T;.;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.68

.;T;T;.;T;T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.057

T;T;T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L;.;.;.;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.95

.;.;N;N;.;N;.

REVEL

Benign

0.051

Sift

Benign

0.50

.;.;T;T;.;T;.

Sift4G

Benign

0.99

T;T;T;T;T;T;T

Polyphen

0.027

.;B;.;.;.;.;.

Vest4

0.080

MutPred

0.15

Gain of glycosylation at A303 (P = 0.0234);Gain of glycosylation at A303 (P = 0.0234);Gain of glycosylation at A303 (P = 0.0234);.;.;.;Gain of glycosylation at A303 (P = 0.0234);

MVP

0.26

MPC

0.11

ClinPred

0.066

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.027

gMVP

0.29

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over