11-13372369-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001297719.2(BMAL1):​c.1027C>T​(p.Arg343Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BMAL1
NM_001297719.2 missense

Scores

14
2
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.60
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BMAL1NM_001297719.2 linkc.1027C>T p.Arg343Trp missense_variant Exon 13 of 20 ENST00000403290.6 NP_001284648.1 O00327-2B2RCL8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BMAL1ENST00000403290.6 linkc.1027C>T p.Arg343Trp missense_variant Exon 13 of 20 1 NM_001297719.2 ENSP00000384517.1 O00327-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461882
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 29, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1024C>T (p.R342W) alteration is located in exon 13 (coding exon 9) of the ARNTL gene. This alteration results from a C to T substitution at nucleotide position 1024, causing the arginine (R) at amino acid position 342 to be replaced by a tryptophan (W). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
.;.;T;.;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D
MetaSVM
Benign
-0.32
T
MutationAssessor
Pathogenic
3.4
.;.;M;.;.
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-7.5
D;D;D;D;D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;D;D;.;D
Vest4
0.95
MutPred
0.87
.;.;Loss of disorder (P = 0.046);.;.;
MVP
0.74
MPC
1.8
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.84
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-13393916; API