chr11-13356918-G-A

Variant names:

• chr11-13356918-G-A
• rs70965442
• ENST00000403482.7:c.37G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001297719.2(BMAL1):​c.180-137G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,585,270 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 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (22 hom.)
• Consequence: BMAL1 NM_001297719.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.155
• Publications: 1 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]

LOC124902636 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063203573).
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMAL1	NM_001297719.2	c.180-137G>A		intron_variant	Intron 6 of 19	ENST00000403290.6	NP_001284648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMAL1	ENST00000403290.6	c.180-137G>A		intron_variant	Intron 6 of 19	1	NM_001297719.2	ENSP00000384517.1

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00343

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00214 AC: 434 AN: 202922 AF XY: 0.00213

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.000107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000253

Gnomad NFE exome AF: 0.00364

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00440 AC: 6309 AN: 1432944 Hom.: 22 Cov.: 32 AF XY: 0.00429 AC XY: 3046 AN XY: 710652

African (AFR) AF: 0.000801 AC: 26 AN: 32462

American (AMR) AF: 0.00278 AC: 112 AN: 40342

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 37630

South Asian (SAS) AF: 0.000108 AC: 9 AN: 83418

European-Finnish (FIN) AF: 0.000154 AC: 8 AN: 52068

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.00543 AC: 5952 AN: 1096210

Other (OTH) AF: 0.00334 AC: 198 AN: 59300

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74490

African (AFR) AF: 0.00125 AC: 52 AN: 41568

American (AMR) AF: 0.00313 AC: 48 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00343 AC: 233 AN: 68020

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00290 Hom.: 0

Bravo AF: 0.00277

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00649 AC: 25

ExAC AF: 0.00174 AC: 209

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.1
DANN	Benign	0.95
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.15
PROVEAN	Benign	0.20	N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.51	P
Vest4		0.26
MVP		0.25
ClinPred		0.040	T
GERP RS		0.26
PromoterAI		-0.0075	Neutral
Mutation Taster		=100/0	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: rs70965442; hg19: chr11-13378465;