chr17-44189566-G-A

Position:

• chr17-44189566-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001076674.3(TMUB2):​c.580G>A​(p.Asp194Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMUB2 NM_001076674.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.34

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMUB2	NM_001076674.3	c.580G>A	p.Asp194Asn	missense_variant	3/4	ENST00000538716.7	NP_001070142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMUB2	ENST00000538716.7	c.580G>A	p.Asp194Asn	missense_variant	3/4	2	NM_001076674.3	ENSP00000444565	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.580G>A (p.D194N) alteration is located in exon 3 (coding exon 2) of the TMUB2 gene. This alteration results from a G to A substitution at nucleotide position 580, causing the aspartic acid (D) at amino acid position 194 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	.;.;T;T;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;.;D;.;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.5	.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D;D;D;.;D;.;.
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.;D
Vest4		0.84
MutPred		0.71		.;.;Gain of catalytic residue at D194 (P = 0.0787);Gain of catalytic residue at D194 (P = 0.0787);.;.;.;
MVP		0.96
MPC		0.42
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42266934;