17-40100440-G-A

Variant names:

• chr17-40100440-G-A
• rs939347
• NM_021724.5:c.-346C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021724.5(NR1D1):​c.-346C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 458,460 control chromosomes in the GnomAD database, including 18,387 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 0.28 (6702 hom., cov: 33)
  • Exomes 𝑓: 0.26 (11685 hom.)
• Consequence: NR1D1 NM_021724.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 25 publications found

Genes affected

NR1D1 (HGNC:7962): (nuclear receptor subfamily 1 group D member 1) This gene encodes a transcription factor that is a member of the nuclear receptor subfamily 1. The encoded protein is a ligand-sensitive transcription factor that negatively regulates the expression of core clock proteins. In particular this protein represses the circadian clock transcription factor aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL). This protein may also be involved in regulating genes that function in metabolic, inflammatory and cardiovascular processes. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.515 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021724.5. 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
	NR1D1	NM_021724.5	MANE Select	c.-346C>T		5_prime_UTR	Exon 1 of 8	NP_068370.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1D1	ENST00000246672.4	TSL:1 MANE Select	c.-346C>T		5_prime_UTR	Exon 1 of 8	ENSP00000246672.3

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43292 AN: 152092 Hom.: 6691 Cov.: 33

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.182

Gnomad FIN AF: 0.336

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.245

Gnomad OTH AF: 0.251

GnomAD4 exome AF: 0.259 AC: 79468 AN: 306248 Hom.: 11685 Cov.: 0 AF XY: 0.255 AC XY: 40509 AN XY: 158786

African (AFR) AF: 0.349 AC: 3055 AN: 8748

American (AMR) AF: 0.204 AC: 2157 AN: 10552

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 2201 AN: 10340

East Asian (EAS) AF: 0.488 AC: 12061 AN: 24690

South Asian (SAS) AF: 0.159 AC: 2771 AN: 17456

European-Finnish (FIN) AF: 0.313 AC: 7279 AN: 23224

Middle Eastern (MID) AF: 0.190 AC: 283 AN: 1490

European-Non Finnish (NFE) AF: 0.234 AC: 44633 AN: 190686

Other (OTH) AF: 0.264 AC: 5028 AN: 19062

GnomAD4 genome AF: 0.285 AC: 43344 AN: 152212 Hom.: 6702 Cov.: 33 AF XY: 0.285 AC XY: 21181 AN XY: 74424

African (AFR) AF: 0.354 AC: 14714 AN: 41530

American (AMR) AF: 0.220 AC: 3365 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3470

East Asian (EAS) AF: 0.531 AC: 2750 AN: 5178

South Asian (SAS) AF: 0.182 AC: 879 AN: 4826

European-Finnish (FIN) AF: 0.336 AC: 3555 AN: 10596

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.245 AC: 16646 AN: 67994

Other (OTH) AF: 0.250 AC: 528 AN: 2116

Alfa AF: 0.257 Hom.: 10298

Bravo AF: 0.281

Asia WGS AF: 0.342 AC: 1190 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		1.1
PromoterAI		-0.080	Neutral
Mutation Taster		=299/1	polymorphism (auto)

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: rs939347; hg19: chr17-38256693; COSMIC: COSV55859846;