Genetic Variant MCL1:p.Ala28Thr (chr1-150579449-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021960.5(MCL1):c.82G>A(p.Ala28Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,590,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

MCL1
NM_021960.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.634

Publications

0 publications found

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:

ENSG00000290074 (HGNC:):

ENSG00000290074 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09960997).

BS2

High AC in GnomAdExome4 at 47 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021960.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCL1	NM_021960.5	MANE Select	c.82G>A	p.Ala28Thr	missense	Exon 1 of 3	NP_068779.1	Q07820-1
MCL1	NM_182763.3		c.82G>A	p.Ala28Thr	missense	Exon 1 of 2	NP_877495.1	Q07820-2
MCL1	NM_001197320.2		c.82G>A	p.Ala28Thr	missense	Exon 1 of 4	NP_001184249.1	A0A087WT64

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MCL1	ENST00000369026.3	TSL:1 MANE Select	c.82G>A	p.Ala28Thr	missense	Exon 1 of 3	ENSP00000358022.2	Q07820-1
MCL1	ENST00000307940.3	TSL:1	c.82G>A	p.Ala28Thr	missense	Exon 1 of 2	ENSP00000309973.3	Q07820-2
MCL1	ENST00000620947.4	TSL:1	c.82G>A	p.Ala28Thr	missense	Exon 1 of 4	ENSP00000477624.1	A0A087WT64

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

207336

AF XY:

0.0000172

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000331

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000327

AC:

AN:

1438304

Hom.:

Cov.:

AF XY:

0.0000238

AC XY:

AN XY:

715338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30430

American (AMR)

AF:

0.00

AC:

AN:

42398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25304

East Asian (EAS)

AF:

0.00

AC:

AN:

36594

South Asian (SAS)

AF:

0.00

AC:

AN:

84806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000408

AC:

AN:

1102692

Other (OTH)

AF:

0.0000337

AC:

AN:

59270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000175

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.67

M_CAP

Benign

0.016

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.63

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.49

REVEL

Benign

0.039

Sift

Uncertain

0.0040

Sift4G

Benign

0.12

Polyphen

0.013

Vest4

0.090

MutPred

0.22

Gain of glycosylation at A28 (P = 9e-04)

MVP

0.18

MPC

1.5

ClinPred

0.64

GERP RS

1.3

PromoterAI

-0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.11

gMVP

0.24

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over