chr22-35323795-G-A

Variant names:

• chr22-35323795-G-A
• NM_005488.3:c.529G>A

Variant summary

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

The NM_005488.3(TOM1):​c.529G>A​(p.Gly177Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,272 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TOM1 NM_005488.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.111370265).

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.529G>A	p.Gly177Arg	missense	Exon 6 of 15	NP_005479.1	O60784-1
	TOM1	NM_001135732.2		c.529G>A	p.Gly177Arg	missense	Exon 6 of 15	NP_001129204.1	O60784-2
	TOM1	NM_001135729.2		c.430G>A	p.Gly144Arg	missense	Exon 6 of 15	NP_001129201.1	O60784-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOM1	ENST00000449058.7	TSL:1 MANE Select	c.529G>A	p.Gly177Arg	missense	Exon 6 of 15	ENSP00000394466.2	O60784-1
	TOM1	ENST00000411850.5	TSL:1	c.529G>A	p.Gly177Arg	missense	Exon 6 of 15	ENSP00000413697.1	O60784-2
	TOM1	ENST00000953252.1		c.529G>A	p.Gly177Arg	missense	Exon 6 of 16	ENSP00000623311.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460272 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726324

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111144

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome Cov.: 32

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	0.077
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Benign	0.15
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.8
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.074
Sift	Benign	0.57	T
Sift4G	Benign	0.41	T
Polyphen		0.0080	B
Vest4		0.17
MutPred		0.16		Gain of helix (P = 0.0425)
MVP		0.49
MPC		0.35
ClinPred		0.15	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.33
Mutation Taster		=65/35	polymorphism

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

hg19: chr22-35719788;