11-13354326-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001297719.2(BMAL1):c.18G>C(p.Met6Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMAL1 NM_001297719.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.22

Genes affected

BMAL1 (HGNC:701): (basic helix-loop-helix ARNT like 1) The protein encoded by this gene is a basic helix-loop-helix protein that forms a heterodimer with CLOCK. This heterodimer binds E-box enhancer elements upstream of Period (PER1, PER2, PER3) and Cryptochrome (CRY1, CRY2) genes and activates transcription of these genes. PER and CRY proteins heterodimerize and repress their own transcription by interacting in a feedback loop with CLOCK/ARNTL complexes. Defects in this gene have been linked to infertility, problems with gluconeogenesis and lipogenesis, and altered sleep patterns. The protein regulates interferon-stimulated gene expression and is an important factor in viral infection, including COVID-19. [provided by RefSeq, Oct 2021]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BMAL1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMAL1	NM_001297719.2	c.18G>C	p.Met6Ile	missense_variant	5/20	ENST00000403290.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMAL1	ENST00000403290.6	c.18G>C	p.Met6Ile	missense_variant	5/20	1	NM_001297719.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Premature ovarian failure Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano

Mar 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Benign	0.0063	T
MetaRNN	Uncertain	0.47	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.0	D;D;D;N;N;N;N;D
REVEL	Benign	0.23
Sift4G	Pathogenic	0.0	D;D;D;T;T;T;T;D
Polyphen		0.91, 0.85	.;.;.;.;P;.;P;.
Vest4		0.77, 0.79
MutPred		0.18		Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);Gain of catalytic residue at M6 (P = 0.1094);
MVP		0.70
MPC		1.8
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.45
gMVP		0.37

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

Other links and lift over

dbSNP: rs1942174898; hg19: chr11-13375873;