8-120445511-A-G

Position:

• chr8-120445511-A-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.41A>G​(p.Lys14Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MTBP NM_022045.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0310

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=0.059193492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTBP	NM_022045.5	c.41A>G	p.Lys14Arg	missense_variant	1/22	ENST00000305949.6	NP_071328.2
MTBP	XM_011516962.3	c.41A>G	p.Lys14Arg	missense_variant	1/18		XP_011515264.1
MTBP	XM_011516963.3	c.41A>G	p.Lys14Arg	missense_variant	1/14		XP_011515265.1
MTBP	XR_928318.3	n.93A>G		non_coding_transcript_exon_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTBP	ENST00000305949.6	c.41A>G	p.Lys14Arg	missense_variant	1/22	1	NM_022045.5	ENSP00000303398	P1
MTBP	ENST00000456899.6	n.112A>G		non_coding_transcript_exon_variant	1/3	3
MTBP	ENST00000522308.1	n.90A>G		non_coding_transcript_exon_variant	1/4	2
MTBP	ENST00000523373.5	c.41A>G	p.Lys14Arg	missense_variant, NMD_transcript_variant	1/11	5		ENSP00000430771

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461326 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Feb 27, 2024

The c.41A>G (p.K14R) alteration is located in exon 1 (coding exon 1) of the MTBP gene. This alteration results from a A to G substitution at nucleotide position 41, causing the lysine (K) at amino acid position 14 to be replaced by an arginine (R). 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	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.0040
Sift	Benign	0.11	T
Sift4G	Benign	0.21	T
Polyphen		0.0080	B
Vest4		0.13
MutPred		0.30		Loss of methylation at K14 (P = 0.0075);
MVP		0.30
MPC		0.14
ClinPred		0.098	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1813203517; hg19: chr8-121457751;