NM_005486.3:c.1240G>C

Variant names:

• chr17-54949575-G-C
• rs150430773
• NM_005486.3:c.1240G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005486.3(TOM1L1):​c.1240G>C​(p.Ala414Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 1,613,976 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (2 hom.)
• Consequence: TOM1L1 NM_005486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012107104).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005486.3. 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
	TOM1L1	NM_005486.3	MANE Select	c.1240G>C	p.Ala414Pro	missense	Exon 13 of 16	NP_005477.2	O75674-1
	TOM1L1	NM_001321174.2		c.1009G>C	p.Ala337Pro	missense	Exon 11 of 14	NP_001308103.1	O75674-3
	TOM1L1	NM_001321175.2		c.1009G>C	p.Ala337Pro	missense	Exon 14 of 17	NP_001308104.1	O75674-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOM1L1	ENST00000575882.6	TSL:1 MANE Select	c.1240G>C	p.Ala414Pro	missense	Exon 13 of 16	ENSP00000460823.1	O75674-1
	TOM1L1	ENST00000851795.1		c.1240G>C	p.Ala414Pro	missense	Exon 13 of 17	ENSP00000521854.1
	TOM1L1	ENST00000851789.1		c.1240G>C	p.Ala414Pro	missense	Exon 13 of 16	ENSP00000521848.1

Frequencies

GnomAD3 genomes AF: 0.000605 AC: 92 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000486 AC: 122 AN: 250982 AF XY: 0.000523

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.000829

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000654 AC: 956 AN: 1461774 Hom.: 2 Cov.: 31 AF XY: 0.000675 AC XY: 491 AN XY: 727190

African (AFR) AF: 0.0000896 AC: 3 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.000843 AC: 45 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000794 AC: 883 AN: 1111930

Other (OTH) AF: 0.000166 AC: 10 AN: 60394

GnomAD4 genome AF: 0.000604 AC: 92 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74384

African (AFR) AF: 0.000168 AC: 7 AN: 41548

American (AMR) AF: 0.000196 AC: 3 AN: 15282

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00161 AC: 17 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68034

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000698 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000763

EpiControl AF: 0.000771

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	0.081
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.046
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.028	B
Vest4		0.53
MVP		0.30
MPC		0.16
ClinPred		0.023	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.42
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs150430773; hg19: chr17-53026936;