rs70965441

Variant names:

• chr11-13310021-A-C
• rs70965441
• NM_001297719.2:c.-228A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001297719.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL1	NM_001297719.2	MANE Select	c.-228A>C		5_prime_UTR	Exon 2 of 20	NP_001284648.1
	BMAL1	NR_147785.2		n.169A>C		non_coding_transcript_exon	Exon 2 of 19
	BMAL1	NR_147786.2		n.169A>C		non_coding_transcript_exon	Exon 2 of 19

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMAL1	ENST00000403290.6	TSL:1 MANE Select	c.-228A>C		5_prime_UTR	Exon 2 of 20	ENSP00000384517.1
	BMAL1	ENST00000389707.8	TSL:1	c.-228A>C		5_prime_UTR	Exon 2 of 20	ENSP00000374357.4
	BMAL1	ENST00000401424.6	TSL:1	c.-373A>C		5_prime_UTR	Exon 2 of 20	ENSP00000385915.2

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0161 AC: 7 AN: 434

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.00445 AC: 185 AN: 41572

American (AMR) AF: 0.00372 AC: 57 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00933 AC: 45 AN: 4824

European-Finnish (FIN) AF: 0.0188 AC: 200 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1632 AN: 68024

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.85
PhyloP100		-0.037
PromoterAI		0.0093	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs70965441; hg19: chr11-13331568;