Variant 1-150579224-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021960.5(MCL1):c.307C>T(p.Arg103Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000492 in 1,564,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

MCL1
NM_021960.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.126

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06928575).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MCL1	NM_021960.5 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	1/3	ENST00000369026.3	NP_068779.1
MCL1	NM_182763.3 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	1/2		NP_877495.1
MCL1	NM_001197320.2 linkuse as main transcript	c.108+199C>T		intron_variant			NP_001184249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCL1	ENST00000369026.3 linkuse as main transcript	c.307C>T	p.Arg103Cys	missense_variant	1/3	1	NM_021960.5	ENSP00000358022	P1	Q07820-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

187220

Hom.:

AF XY:

0.0000477

AC XY:

AN XY:

104784

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000820

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000489

AC:

AN:

1412358

Hom.:

Cov.:

AF XY:

0.0000400

AC XY:

AN XY:

700024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000268

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:

0.0000613

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000257

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.307C>T (p.R103C) alteration is located in exon 1 (coding exon 1) of the MCL1 gene. This alteration results from a C to T substitution at nucleotide position 307, causing the arginine (R) at amino acid position 103 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.46

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.15

N;N

REVEL

Benign

0.091

Sift

Benign

0.056

T;D

Sift4G

Uncertain

0.024

D;D

Polyphen

0.0020

B;B

Vest4

0.22

MutPred

0.19

Loss of methylation at R103 (P = 0.0228);Loss of methylation at R103 (P = 0.0228);

MVP

0.20

MPC

0.77

ClinPred

0.058

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.087

gMVP

0.22

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