1-150579224-G-T

Variant names:

• chr1-150579224-G-T
• rs773052989
• NM_021960.5:c.307C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021960.5(MCL1):​c.307C>A​(p.Arg103Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. R103C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MCL1 NM_021960.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.126
• Publications: 0 publications found

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]

ENSG00000290074 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080501616).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCL1	NM_021960.5	MANE Select	c.307C>A	p.Arg103Ser	missense	Exon 1 of 3	NP_068779.1	Q07820-1
	MCL1	NM_182763.3		c.307C>A	p.Arg103Ser	missense	Exon 1 of 2	NP_877495.1	Q07820-2
	MCL1	NM_001197320.2		c.108+199C>A		intron	N/A	NP_001184249.1	A0A087WT64

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCL1	ENST00000369026.3	TSL:1 MANE Select	c.307C>A	p.Arg103Ser	missense	Exon 1 of 3	ENSP00000358022.2	Q07820-1
	MCL1	ENST00000307940.3	TSL:1	c.307C>A	p.Arg103Ser	missense	Exon 1 of 2	ENSP00000309973.3	Q07820-2
	MCL1	ENST00000620947.4	TSL:1	c.108+199C>A		intron	N/A	ENSP00000477624.1	A0A087WT64

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1412358 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 700024

African (AFR) AF: 0.00 AC: 0 AN: 31734

American (AMR) AF: 0.00 AC: 0 AN: 37268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23522

East Asian (EAS) AF: 0.00 AC: 0 AN: 38868

South Asian (SAS) AF: 0.00 AC: 0 AN: 81158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5536

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092208

Other (OTH) AF: 0.00 AC: 0 AN: 58196

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.13
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.10
Sift	Uncertain	0.012	D
Sift4G	Benign	0.10	T
Polyphen		0.0040	B
Vest4		0.15
MutPred		0.16		Gain of glycosylation at R103 (P = 0.013)
MVP		0.17
MPC		0.64
ClinPred		0.088	T
GERP RS		1.8
PromoterAI		-0.041	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.13
gMVP		0.27
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773052989; hg19: chr1-150551700;