8-120463714-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022045.5(MTBP):c.1000C>G(p.Gln334Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000014 (0 hom.)
• Consequence: MTBP NM_022045.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01

Genes affected

MTBP (HGNC:7417): (MDM2 binding protein) This gene encodes a protein that interacts with the oncoprotein mouse double minute 2. The encoded protein regulates progression through the cell cycle and may be involved in tumor formation. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037898272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTBP	NM_022045.5	c.1000C>G	p.Gln334Glu	missense_variant	10/22	ENST00000305949.6
MTBP	XM_011516962.3	c.1000C>G	p.Gln334Glu	missense_variant	10/18
MTBP	XM_011516963.3	c.1000C>G	p.Gln334Glu	missense_variant	10/14
MTBP	XR_928318.3	n.1052C>G		non_coding_transcript_exon_variant	10/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTBP	ENST00000305949.6	c.1000C>G	p.Gln334Glu	missense_variant	10/22	1	NM_022045.5	P1
MTBP	ENST00000522449.1	n.197C>G		non_coding_transcript_exon_variant	3/4	1
MTBP	ENST00000523373.5	c.*15C>G		3_prime_UTR_variant, NMD_transcript_variant	10/11	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251180 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135778

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459540 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726108

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Dec 19, 2023

The c.1000C>G (p.Q334E) alteration is located in exon 10 (coding exon 10) of the MTBP gene. This alteration results from a C to G substitution at nucleotide position 1000, causing the glutamine (Q) at amino acid position 334 to be replaced by a glutamic acid (E). 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	Benign	0.062
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	15
Dann	Benign	0.42
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.012
Sift	Benign	0.77	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.19		Gain of disorder (P = 0.0813);
MVP		0.36
MPC		0.50
ClinPred		0.019	T
GERP RS		2.1
Varity_R		0.050
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1339139176; hg19: chr8-121475954;