8-120453852-A-G

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.431A>G(p.Tyr144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,572,622 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (30 hom.)
• Consequence: MTBP NM_022045.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.20

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=0.010437548).
• BP6: Variant 8-120453852-A-G is Benign according to our data. Variant chr8-120453852-A-G is described in ClinVar as [Benign]. Clinvar id is 774248.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1213/152202) while in subpopulation AFR AF= 0.0216 (898/41558). AF 95% confidence interval is 0.0204. There are 14 homozygotes in gnomad4. There are 583 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTBP	NM_022045.5	c.431A>G	p.Tyr144Cys	missense_variant	5/22	ENST00000305949.6
MTBP	XM_011516962.3	c.431A>G	p.Tyr144Cys	missense_variant	5/18
MTBP	XM_011516963.3	c.431A>G	p.Tyr144Cys	missense_variant	5/14
MTBP	XR_928318.3	n.483A>G		non_coding_transcript_exon_variant	5/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTBP	ENST00000305949.6	c.431A>G	p.Tyr144Cys	missense_variant	5/22	1	NM_022045.5	P1
MTBP	ENST00000523373.5	c.431A>G	p.Tyr144Cys	missense_variant, NMD_transcript_variant	5/11	5

Frequencies

GnomAD3 genomes AF: 0.00795 AC: 1209 AN: 152082 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00395 AC: 951 AN: 240620 Hom.: 5 AF XY: 0.00374 AC XY: 487 AN XY: 130300

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.00577

Gnomad ASJ exome AF: 0.00518

Gnomad EAS exome AF: 0.0000579

Gnomad SAS exome AF: 0.00305

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00232

Gnomad OTH exome AF: 0.00784

GnomAD4 exome AF: 0.00248 AC: 3523 AN: 1420420 Hom.: 30 Cov.: 25 AF XY: 0.00255 AC XY: 1805 AN XY: 707600

Gnomad4 AFR exome AF: 0.0227

Gnomad4 AMR exome AF: 0.00603

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.0000781

Gnomad4 SAS exome AF: 0.00396

Gnomad4 FIN exome AF: 0.0000949

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00608

GnomAD4 genome AF: 0.00797 AC: 1213 AN: 152202 Hom.: 14 Cov.: 32 AF XY: 0.00784 AC XY: 583 AN XY: 74408

Gnomad4 AFR AF: 0.0216

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00379 Hom.: 11

Bravo AF: 0.00944

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0170 AC: 75

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00425 AC: 516

Asia WGS AF: 0.00319 AC: 11 AN: 3464

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

Aug 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.79
MVP		0.51
MPC		0.33
ClinPred		0.038	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.42

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: rs141824798; hg19: chr8-121466092; COSMIC: COSV59961692; COSMIC: COSV59961692;