22-35299978-T-G

Variant names:

• chr22-35299978-T-G
• rs1396819307
• NM_005488.3:c.50T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005488.3(TOM1):​c.50T>G​(p.Ile17Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000254 in 1,574,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TOM1 NM_005488.3 missense, splice_region
• Scores: Splicing: ADA: 0.8362
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• Publications: 0 publications found

Genes affected

TOM1 (HGNC:11982): (target of myb1 membrane trafficking protein) This gene was identified as a target of the v-myb oncogene. The encoded protein shares its N-terminal domain in common with proteins associated with vesicular trafficking at the endosome. It is recruited to the endosomes by its interaction with endofin. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

TOM1 Gene-Disease associations (from GenCC):

• immune system disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• immunodeficiency 85 and autoimmunity

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005488.3. 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
	TOM1	NM_005488.3	MANE Select	c.50T>G	p.Ile17Ser	missense splice_region	Exon 1 of 15	NP_005479.1	O60784-1
	TOM1	NM_001135732.2		c.50T>G	p.Ile17Ser	missense splice_region	Exon 1 of 15	NP_001129204.1	O60784-2
	TOM1	NM_001135730.2		c.50T>G	p.Ile17Ser	missense splice_region	Exon 1 of 14	NP_001129202.1	O60784-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOM1	ENST00000449058.7	TSL:1 MANE Select	c.50T>G	p.Ile17Ser	missense splice_region	Exon 1 of 15	ENSP00000394466.2	O60784-1
	TOM1	ENST00000411850.5	TSL:1	c.50T>G	p.Ile17Ser	missense splice_region	Exon 1 of 15	ENSP00000413697.1	O60784-2
	TOM1	ENST00000953252.1		c.50T>G	p.Ile17Ser	missense splice_region	Exon 1 of 16	ENSP00000623311.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1421954 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 703832

African (AFR) AF: 0.00 AC: 0 AN: 32622

American (AMR) AF: 0.00 AC: 0 AN: 39134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25390

East Asian (EAS) AF: 0.00 AC: 0 AN: 37642

South Asian (SAS) AF: 0.00 AC: 0 AN: 81538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090858

Other (OTH) AF: 0.0000170 AC: 1 AN: 58732

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152254 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.022	B
Vest4		0.93
MutPred		0.79		Loss of catalytic residue at I17 (P = 0.0015)
MVP		0.68
MPC		0.44
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.79
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.56
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: rs1396819307; hg19: chr22-35695971;