17-44189276-C-A

Variant names:

• chr17-44189276-C-A
• rs369440160
• NM_001076674.3:c.290C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001076674.3(TMUB2):​c.290C>A​(p.Thr97Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,604,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T97A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TMUB2 NM_001076674.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73
• Publications: 0 publications found

Genes affected

TMUB2 (HGNC:28459): (transmembrane and ubiquitin like domain containing 2) Predicted to be involved in ubiquitin-dependent ERAD pathway. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04397258).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001076674.3. 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
	TMUB2	NM_001076674.3	MANE Select	c.290C>A	p.Thr97Asn	missense	Exon 3 of 4	NP_001070142.1	Q71RG4-1
	TMUB2	NM_001353177.2		c.290C>A	p.Thr97Asn	missense	Exon 3 of 4	NP_001340106.1	Q71RG4-1
	TMUB2	NM_001353181.2		c.290C>A	p.Thr97Asn	missense	Exon 2 of 3	NP_001340110.1	Q71RG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMUB2	ENST00000538716.7	TSL:2 MANE Select	c.290C>A	p.Thr97Asn	missense	Exon 3 of 4	ENSP00000444565.1	Q71RG4-1
	TMUB2	ENST00000319511.6	TSL:1	c.230C>A	p.Thr77Asn	missense	Exon 2 of 3	ENSP00000313214.5	Q71RG4-2
	TMUB2	ENST00000357984.7	TSL:1	c.230C>A	p.Thr77Asn	missense	Exon 2 of 3	ENSP00000350672.3	Q71RG4-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241324 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452070 Hom.: 0 Cov.: 34 AF XY: 0.00000554 AC XY: 4 AN XY: 721460

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106394

Other (OTH) AF: 0.0000333 AC: 2 AN: 59984

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152316 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.056
Sift	Benign	0.11	T
Sift4G	Benign	0.46	T
Polyphen		0.019	B
Vest4		0.12
MutPred		0.19		Loss of glycosylation at T97 (P = 3e-04)
MVP		0.39
MPC		0.082
ClinPred		0.27	T
GERP RS		3.1
PromoterAI		0.0051	Neutral
Varity_R		0.096
gMVP		0.19
Mutation Taster		=87/13	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: rs369440160; hg19: chr17-42266644;