rs70965441

Positions:

• chr11-13310021-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001297719.2(BMAL1):​c.-228A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 152,776 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.016 (0 hom.)
• Consequence: BMAL1 NM_001297719.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0370

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0142 (2167/152330) while in subpopulation NFE AF= 0.024 (1632/68024). AF 95% confidence interval is 0.023. There are 24 homozygotes in gnomad4. There are 1023 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMAL1	NM_001297719.2	c.-228A>C		5_prime_UTR_variant	2/20	ENST00000403290.6	NP_001284648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMAL1	ENST00000403290.6	c.-228A>C		5_prime_UTR_variant	2/20	1	NM_001297719.2	ENSP00000384517	P4

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2170 AN: 152212 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00446

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.00907

GnomAD4 exome AF: 0.0157 AC: 7 AN: 446 Hom.: 0 Cov.: 0 AF XY: 0.00373 AC XY: 1 AN XY: 268

Gnomad4 FIN exome AF: 0.0161

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0142 AC: 2167 AN: 152330 Hom.: 24 Cov.: 32 AF XY: 0.0137 AC XY: 1023 AN XY: 74496

Gnomad4 AFR AF: 0.00445

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00933

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0181 Hom.: 7

Bravo AF: 0.0126

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.85

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: rs70965441; hg19: chr11-13331568;