17-40095638-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021724.5(NR1D1):c.1054A>G(p.Asn352Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR1D1 NM_021724.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR1D1	NM_021724.5	c.1054A>G	p.Asn352Asp	missense_variant	5/8	ENST00000246672.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR1D1	ENST00000246672.4	c.1054A>G	p.Asn352Asp	missense_variant	5/8	1	NM_021724.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.1054A>G (p.N352D) alteration is located in exon 5 (coding exon 5) of the NR1D1 gene. This alteration results from a A to G substitution at nucleotide position 1054, causing the asparagine (N) at amino acid position 352 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.093
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.53	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.35
Sift	Benign	0.25	T
Sift4G	Benign	0.49	T
Polyphen		0.80	P
Vest4		0.61
MutPred		0.29		Gain of helix (P = 0.0854);
MVP		0.64
MPC		0.047
ClinPred		0.57	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38251891;