8-120488225-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_022045.5(MTBP):c.1232G>A(p.Arg411Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,597,048 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (34 hom.)
• Consequence: MTBP NM_022045.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.54

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029696822).
• BP6: Variant 8-120488225-G-A is Benign according to our data. Variant chr8-120488225-G-A is described in ClinVar as [Benign]. Clinvar id is 768261.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0136 (2077/152304) while in subpopulation AFR AF= 0.0459 (1908/41578). AF 95% confidence interval is 0.0442. There are 43 homozygotes in gnomad4. There are 987 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTBP	NM_022045.5	c.1232G>A	p.Arg411Lys	missense_variant	12/22	ENST00000305949.6
MTBP	XM_011516962.3	c.1232G>A	p.Arg411Lys	missense_variant	12/18
MTBP	XM_011516963.3	c.1232G>A	p.Arg411Lys	missense_variant	12/14
MTBP	XR_928318.3	n.1284G>A		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTBP	ENST00000305949.6	c.1232G>A	p.Arg411Lys	missense_variant	12/22	1	NM_022045.5	P1
MTBP	ENST00000519188.1	n.65G>A		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2068 AN: 152186 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00334 AC: 782 AN: 234412 Hom.: 17 AF XY: 0.00234 AC XY: 298 AN XY: 127146

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000257

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00271

GnomAD4 exome AF: 0.00133 AC: 1915 AN: 1444744 Hom.: 34 Cov.: 30 AF XY: 0.00119 AC XY: 858 AN XY: 718288

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.00296

Gnomad4 ASJ exome AF: 0.000309

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.000328

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.0136 AC: 2077 AN: 152304 Hom.: 43 Cov.: 32 AF XY: 0.0133 AC XY: 987 AN XY: 74478

Gnomad4 AFR AF: 0.0459

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00273 Hom.: 11

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0433 AC: 191

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00429 AC: 521

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.17
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.14
Sift	Benign	0.34	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.36
MPC		0.16
ClinPred		0.015	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs79766434; hg19: chr8-121500465; COSMIC: COSV99045443;