rs769737403

Variant names:

• chr17-54914718-C-G
• rs769737403
• NM_005486.3:c.578C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-54914718-C-G
• chr17-54914718-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005486.3(TOM1L1):​c.578C>G​(p.Ser193Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S193L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TOM1L1 NM_005486.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15415174).

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.578C>G	p.Ser193Trp	missense	Exon 6 of 16	NP_005477.2	O75674-1
	TOM1L1	NM_001321174.2		c.347C>G	p.Ser116Trp	missense	Exon 4 of 14	NP_001308103.1	O75674-3
	TOM1L1	NM_001321175.2		c.347C>G	p.Ser116Trp	missense	Exon 7 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.578C>G	p.Ser193Trp	missense	Exon 6 of 16	ENSP00000460823.1	O75674-1
	TOM1L1	ENST00000575333.5	TSL:1	c.578C>G	p.Ser193Trp	missense	Exon 6 of 10	ENSP00000458918.1	O75674-2
	TOM1L1	ENST00000576932.5	TSL:1	n.347C>G		non_coding_transcript_exon	Exon 4 of 11	ENSP00000461876.1	I3NI44

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460980 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726860

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111284

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.082
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		0.98	D
Vest4		0.29
MutPred		0.41		Loss of disorder (P = 4e-04)
MVP		0.46
MPC		0.48
ClinPred		0.41	T
GERP RS		3.6
Varity_R		0.047
gMVP		0.52

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: rs769737403; hg19: chr17-52992079;