NM_021724.5:c.1062C>T

Variant names:

• chr17-40095630-G-A
• rs61736536
• NM_021724.5:c.1062C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021724.5(NR1D1):​c.1062C>T​(p.Ala354Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,612,150 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (15 hom.)
• Consequence: NR1D1 NM_021724.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.173
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-40095630-G-A is Benign according to our data. Variant chr17-40095630-G-A is described in ClinVar as Benign. ClinVar VariationId is 780425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.173 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0074 (1127/152266) while in subpopulation AFR AF = 0.0259 (1075/41530). AF 95% confidence interval is 0.0246. There are 18 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1127 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1D1	NM_021724.5	MANE Select	c.1062C>T	p.Ala354Ala	synonymous	Exon 5 of 8	NP_068370.1	P20393

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR1D1	ENST00000246672.4	TSL:1 MANE Select	c.1062C>T	p.Ala354Ala	synonymous	Exon 5 of 8	ENSP00000246672.3	P20393

Frequencies

GnomAD3 genomes AF: 0.00728 AC: 1108 AN: 152148 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00202 AC: 505 AN: 249968 AF XY: 0.00140

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000796

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000776 AC: 1133 AN: 1459884 Hom.: 15 Cov.: 37 AF XY: 0.000679 AC XY: 493 AN XY: 725974

African (AFR) AF: 0.0255 AC: 855 AN: 33468

American (AMR) AF: 0.00141 AC: 63 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26010

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39654

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.0000576 AC: 64 AN: 1110768

Other (OTH) AF: 0.00224 AC: 135 AN: 60294

GnomAD4 genome AF: 0.00740 AC: 1127 AN: 152266 Hom.: 18 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74456

African (AFR) AF: 0.0259 AC: 1075 AN: 41530

American (AMR) AF: 0.00196 AC: 30 AN: 15302

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00350 Hom.: 1

Bravo AF: 0.00817

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.8
DANN	Benign	0.81
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs61736536; hg19: chr17-38251883;