dbSNP rs151065075: MCL1:p.Met120Leu (chr1-150579173-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_021960.5(MCL1):c.358A>T(p.Met120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M120V) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MCL1
NM_021960.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10617569).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCL1	NM_021960.5 link	c.358A>T	p.Met120Leu	missense_variant	Exon 1 of 3	ENST00000369026.3	NP_068779.1	Q07820-1
MCL1	NM_182763.3 link	c.358A>T	p.Met120Leu	missense_variant	Exon 1 of 2		NP_877495.1	Q07820-2
MCL1	NM_001197320.2 link	c.109-210A>T		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>T	p.Met120Leu	missense_variant	Exon 1 of 3	1	NM_021960.5	ENSP00000358022.2		Q07820-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000418

AC:

AN:

239128

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000559

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1455448

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723854

show subpopulations

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.97

L;L

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.35

N;N

REVEL

Benign

0.070

Sift

Benign

0.14

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.0040

B;B

Vest4

0.28

MutPred

0.22

Loss of catalytic residue at M120 (P = 0.0083);Loss of catalytic residue at M120 (P = 0.0083);

MVP

0.26

MPC

0.53

ClinPred

0.068

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.19

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over