11-13354314-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001297719.2(BMAL1):c.6A>T(p.Ala2=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,604,866 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (18 hom.)
• Consequence: BMAL1 NM_001297719.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-13354314-A-T is Benign according to our data. Variant chr11-13354314-A-T is described in ClinVar as [Benign]. Clinvar id is 709842.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00759 (1153/151910) while in subpopulation AFR AF= 0.0265 (1098/41426). AF 95% confidence interval is 0.0252. There are 18 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMAL1	NM_001297719.2	c.6A>T	p.Ala2=	synonymous_variant	5/20	ENST00000403290.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMAL1	ENST00000403290.6	c.6A>T	p.Ala2=	synonymous_variant	5/20	1	NM_001297719.2	P4

Frequencies

GnomAD3 genomes AF: 0.00757 AC: 1149 AN: 151792 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00243

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00196 AC: 474 AN: 241374 Hom.: 10 AF XY: 0.00147 AC XY: 191 AN XY: 130064

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000343

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000737 AC: 1071 AN: 1452956 Hom.: 18 Cov.: 32 AF XY: 0.000633 AC XY: 457 AN XY: 721976

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000271

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00759 AC: 1153 AN: 151910 Hom.: 18 Cov.: 32 AF XY: 0.00734 AC XY: 545 AN XY: 74264

Gnomad4 AFR AF: 0.0265

Gnomad4 AMR AF: 0.00243

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.000851 Hom.: 0

Bravo AF: 0.00897

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	3.9
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75830309; hg19: chr11-13375861;