Genetic Variant BMAL1:p.Val13Leu (chr11-13356918-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000403482.7(BMAL1):c.37G>C(p.Val13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,432,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 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: not found (cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

BMAL1
ENST00000403482.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.155

Publications

0 publications found

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]

BMAL1 links:

LOC124902636 (HGNC:):

LOC124902636 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06308821).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000403482.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
BMAL1	NM_001297719.2	MANE Select	c.180-137G>C	intron	N/A	NP_001284648.1
BMAL1	NM_001351807.2		c.180-137G>C	intron	N/A	NP_001338736.1
BMAL1	NM_001351814.2		c.180-137G>C	intron	N/A	NP_001338743.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BMAL1	ENST00000403482.7	TSL:1	c.37G>C	p.Val13Leu	missense	Exon 1 of 14	ENSP00000385897.3
BMAL1	ENST00000403290.6	TSL:1 MANE Select	c.180-137G>C		intron	N/A	ENSP00000384517.1
BMAL1	ENST00000389707.8	TSL:1	c.180-137G>C		intron	N/A	ENSP00000374357.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1432944

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32462

American (AMR)

AF:

0.00

AC:

AN:

40342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25770

East Asian (EAS)

AF:

0.00

AC:

AN:

37630

South Asian (SAS)

AF:

0.00

AC:

AN:

83418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1096210

Other (OTH)

AF:

0.00

AC:

AN:

59300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

2.7

(source)

DANN

Benign

0.95

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.38

M_CAP

Benign

0.0040

MetaRNN

Benign

0.063

MetaSVM

Benign

-0.94

PhyloP100

0.15

PROVEAN

Benign

-0.050

REVEL

Benign

0.035

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.013

Vest4

0.095

MutPred

0.32

Loss of catalytic residue at V13 (P = 0.1349)

MVP

0.18

ClinPred

0.20

GERP RS

0.26

PromoterAI

0.00040

Neutral

(source)

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over