22-35300084-G-A

Variant names:

• chr22-35300084-G-A
• rs138728
• NM_005488.3:c.52+104G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005488.3(TOM1):​c.52+104G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0512 in 1,336,382 control chromosomes in the GnomAD database, including 2,552 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (775 hom., cov: 35)
  • Exomes 𝑓: 0.047 (1777 hom.)
• Consequence: TOM1 NM_005488.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

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.52+104G>A		intron	N/A	NP_005479.1	O60784-1
	TOM1	NM_001135732.2		c.52+104G>A		intron	N/A	NP_001129204.1	O60784-2
	TOM1	NM_001135729.2		c.-48+706G>A		intron	N/A	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.52+104G>A		intron	N/A	ENSP00000394466.2	O60784-1
	TOM1	ENST00000411850.5	TSL:1	c.52+104G>A		intron	N/A	ENSP00000413697.1	O60784-2
	TOM1	ENST00000953252.1		c.52+104G>A		intron	N/A	ENSP00000623311.1

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12226 AN: 152156 Hom.: 771 Cov.: 35

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0339

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0782

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0458

Gnomad OTH AF: 0.0569

GnomAD4 exome AF: 0.0475 AC: 56211 AN: 1184108 Hom.: 1777 AF XY: 0.0464 AC XY: 27463 AN XY: 592090

African (AFR) AF: 0.187 AC: 5011 AN: 26808

American (AMR) AF: 0.0222 AC: 720 AN: 32402

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 379 AN: 22724

East Asian (EAS) AF: 0.0772 AC: 2661 AN: 34456

South Asian (SAS) AF: 0.0304 AC: 2250 AN: 73976

European-Finnish (FIN) AF: 0.0324 AC: 1244 AN: 38380

Middle Eastern (MID) AF: 0.0197 AC: 86 AN: 4356

European-Non Finnish (NFE) AF: 0.0457 AC: 41124 AN: 900240

Other (OTH) AF: 0.0539 AC: 2736 AN: 50766

GnomAD4 genome AF: 0.0806 AC: 12270 AN: 152274 Hom.: 775 Cov.: 35 AF XY: 0.0773 AC XY: 5759 AN XY: 74456

African (AFR) AF: 0.181 AC: 7513 AN: 41542

American (AMR) AF: 0.0339 AC: 519 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.0782 AC: 405 AN: 5178

South Asian (SAS) AF: 0.0308 AC: 149 AN: 4830

European-Finnish (FIN) AF: 0.0353 AC: 374 AN: 10608

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0458 AC: 3115 AN: 68016

Other (OTH) AF: 0.0563 AC: 119 AN: 2112

Alfa AF: 0.0404 Hom.: 973

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.3
DANN	Benign	0.96
PhyloP100		-1.1
PromoterAI		-0.012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs138728; hg19: chr22-35696077;