Genetic Variant NM_016459.4:c.50T>C (chr5-139389807-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_016459.4(MZB1):c.50T>C(p.Ile17Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,550,662 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0090 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 13 hom. )

Consequence

MZB1
NM_016459.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0970

Variant links:

Genes affected

MZB1 (HGNC:30125): (marginal zone B and B1 cell specific protein) Involved in positive regulation of cell population proliferation. Located in cytoplasm and extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

MZB1 links:

ENSG00000302512 (HGNC:):

ENSG00000302512 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024272501).

BP6

Variant 5-139389807-A-G is Benign according to our data. Variant chr5-139389807-A-G is described in ClinVar as [Benign]. Clinvar id is 780565.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00895 (1363/152230) while in subpopulation AFR AF = 0.0293 (1215/41534). AF 95% confidence interval is 0.0279. There are 17 homozygotes in GnomAd4. There are 657 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MZB1	NM_016459.4 link	c.50T>C	p.Ile17Thr	missense_variant	Exon 1 of 4	ENST00000302125.9	NP_057543.2	Q8WU39-1
MZB1	XM_047417264.1 link	c.-304T>C		5_prime_UTR_variant	Exon 1 of 5		XP_047273220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MZB1	ENST00000302125.9 link	c.50T>C	p.Ile17Thr	missense_variant	Exon 1 of 4	1	NM_016459.4	ENSP00000303920.8		Q8WU39-1

Frequencies

GnomAD3 genomes

AF:

0.00882

AC:

1342

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0288

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00816

GnomAD2 exomes

AF:

0.00270

AC:

415

AN:

153668

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.0329

Gnomad AMR exome

AF:

0.00170

Gnomad ASJ exome

AF:

0.00318

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000882

Gnomad OTH exome

AF:

0.00368

GnomAD4 exome

AF:

0.00136

AC:

1907

AN:

1398432

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

875

AN XY:

689706

show subpopulations

African (AFR)

AF:

0.0290

AC:

918

AN:

31614

American (AMR)

AF:

0.00202

AC:

AN:

35710

Ashkenazi Jewish (ASJ)

AF:

0.00338

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35750

South Asian (SAS)

AF:

0.000480

AC:

AN:

79240

European-Finnish (FIN)

AF:

0.0000623

AC:

AN:

48136

Middle Eastern (MID)

AF:

0.0173

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.000476

AC:

514

AN:

1079122

Other (OTH)

AF:

0.00309

AC:

179

AN:

58016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

118

236

354

472

590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00895

AC:

1363

AN:

152230

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

657

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0293

AC:

1215

AN:

41534

American (AMR)

AF:

0.00347

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68000

Other (OTH)

AF:

0.00807

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00645

Hom.:

Bravo

AF:

0.00967

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0204

AC:

ESP6500EA

AF:

0.000611

AC:

ExAC

AF:

0.00198

AC:

171

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 11, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.022

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

PhyloP100

0.097

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.030

REVEL

Benign

0.026

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.0090

Polyphen

0.16

Vest4

0.11

MVP

0.32

MPC

0.059

ClinPred

0.013

GERP RS

1.0

PromoterAI

0.0099

Neutral

(source)

Varity_R

0.066

gMVP

0.14

Mutation Taster

=96/4

polymorphism

(source)

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

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NM_016459.4:c.50T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over