22-41436315-T-G

Variant names:

• chr22-41436315-T-G
• rs200620356
• NM_016272.4:c.1031A>C

Variant summary

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

The NM_016272.4(TOB2):​c.1031A>C​(p.Asn344Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,718 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N344S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TOB2 NM_016272.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.67
• Publications: 0 publications found

Genes affected

TOB2 (HGNC:11980): (transducer of ERBB2, 2) TOB2 belongs to the TOB (see TOB1; MIM 605523)/BTG1 (MIM 109580) family of antiproliferative proteins, which are involved in the regulation of cell cycle progression.[supplied by OMIM, Apr 2004]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016272.4. 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
	TOB2	NM_016272.4	MANE Select	c.1031A>C	p.Asn344Thr	missense	Exon 2 of 2	NP_057356.1	Q14106-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOB2	ENST00000327492.4	TSL:1 MANE Select	c.1031A>C	p.Asn344Thr	missense	Exon 2 of 2	ENSP00000331305.3	Q14106-1
	TOB2	ENST00000434408.2	TSL:2	c.1031A>C	p.Asn344Thr	missense	Exon 2 of 2	ENSP00000388549.2	Q14106-1
	TOB2	ENST00000901391.1		c.1031A>C	p.Asn344Thr	missense	Exon 2 of 2	ENSP00000571450.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1407718 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 694012

African (AFR) AF: 0.0000312 AC: 1 AN: 32094

American (AMR) AF: 0.00 AC: 0 AN: 37800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22522

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.00 AC: 0 AN: 78696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083242

Other (OTH) AF: 0.00 AC: 0 AN: 57954

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.71
MutPred		0.45		Gain of glycosylation at N344 (P = 0.0591)
MVP		0.17
MPC		1.0
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.69
Mutation Taster		=54/46	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

dbSNP: rs200620356; hg19: chr22-41832319;