Genetic Variant MCL1:p.Met120Val (chr1-150579173-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_021960.5(MCL1):c.358A>G(p.Met120Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,607,750 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00052 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

MCL1
NM_021960.5 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0550

Variant links:

Genes affected

MCL1 (HGNC:6943): (MCL1 apoptosis regulator, BCL2 family member) This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010]

MCL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070598423).

BP6

Variant 1-150579173-T-C is Benign according to our data. Variant chr1-150579173-T-C is described in ClinVar as [Benign]. Clinvar id is 788764.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 79 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCL1	NM_021960.5 link	c.358A>G	p.Met120Val	missense_variant	Exon 1 of 3	ENST00000369026.3	NP_068779.1	Q07820-1
MCL1	NM_182763.3 link	c.358A>G	p.Met120Val	missense_variant	Exon 1 of 2		NP_877495.1	Q07820-2
MCL1	NM_001197320.2 link	c.109-210A>G		intron_variant	Intron 1 of 3		NP_001184249.1	Q07820C8YZ26A0A087WT64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCL1	ENST00000369026.3 link	c.358A>G	p.Met120Val	missense_variant	Exon 1 of 3	1	NM_021960.5	ENSP00000358022.2		Q07820-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000774

AC:

185

AN:

239128

Hom.:

AF XY:

0.000715

AC XY:

AN XY:

131530

show subpopulations

Gnomad AFR exome

AF:

0.0000702

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0135

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000428

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.000484

AC:

705

AN:

1455448

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

342

AN XY:

723854

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.0134

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.00145

GnomAD4 genome

AF:

0.000519

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000969

Hom.:

Bravo

AF:

0.000544

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00107

AC:

ExAC

AF:

0.000706

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

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

0.084

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.59

DEOGEN2

Benign

0.25

T;.

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.0071

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.63

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.21

N;N

REVEL

Benign

0.073

Sift

Benign

0.18

T;T

Sift4G

Benign

0.76

T;T

Polyphen

0.0

B;B

Vest4

0.20

MVP

0.14

MPC

0.57

ClinPred

0.019

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over