Variant chr1-150579419-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021960.5(MCL1):c.112A>T(p.Thr38Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000506 in 1,580,602 control chromosomes in the GnomAD database, including 1 homozygotes. 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.

Frequency

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

Exomes 𝑓: 0.000050 ( 1 hom. )

Consequence

MCL1
NM_021960.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.66

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:

MCL1 (HGNC:):

MCL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030777246).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCL1	NM_021960.5 linkuse as main transcript	c.112A>T	p.Thr38Ser	missense_variant	1/3	ENST00000369026.3	NP_068779.1	Q07820-1
MCL1	NM_182763.3 linkuse as main transcript	c.112A>T	p.Thr38Ser	missense_variant	1/2		NP_877495.1	Q07820-2
MCL1	NM_001197320.2 linkuse as main transcript	c.108+4A>T		splice_region_variant, intron_variant			NP_001184249.1	Q07820C8YZ26A0A087WT64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCL1	ENST00000369026.3 linkuse as main transcript	c.112A>T	p.Thr38Ser	missense_variant	1/3	1	NM_021960.5	ENSP00000358022.2		Q07820-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152080

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:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000472

AC:

AN:

190788

Hom.:

AF XY:

0.0000559

AC XY:

AN XY:

107306

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000348

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:

0.0000969

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000504

AC:

AN:

1428404

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

709992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000333

Gnomad4 AMR exome

AF:

0.0000251

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:

0.0000628

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000473

Alfa

AF:

0.000123

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000439

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

Sep 08, 2024

The c.112A>T (p.T38S) alteration is located in exon 1 (coding exon 1) of the MCL1 gene. This alteration results from a A to T substitution at nucleotide position 112, causing the threonine (T) at amino acid position 38 to be replaced by a serine (S). 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

0.072

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.68

DANN

Benign

0.40

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.0034

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-0.55

N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.0080

Sift

Benign

0.70

T;T

Sift4G

Benign

0.77

T;T

Polyphen

0.0

B;B

Vest4

0.049

MutPred

0.12

Gain of phosphorylation at T38 (P = 0.049);Gain of phosphorylation at T38 (P = 0.049);

MVP

0.38

MPC

0.50

ClinPred

0.039

GERP RS

-1.8

Varity_R

0.031

gMVP

0.082

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