3-23954552-A-C

Variant names:

• chr3-23954552-A-C
• rs750368358
• NM_005126.5:c.32A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005126.5(NR1D2):​c.32A>C​(p.Tyr11Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR1D2 NM_005126.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.06

Genes affected

NR1D2 (HGNC:7963): (nuclear receptor subfamily 1 group D member 2) This gene encodes a member of the nuclear hormone receptor family, specifically the NR1 subfamily of receptors. The encoded protein functions as a transcriptional repressor and may play a role in circadian rhythms and carbohydrate and lipid metabolism. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D2	NM_005126.5	c.32A>C	p.Tyr11Ser	missense_variant	Exon 2 of 8	ENST00000312521.9	NP_005117.3
NR1D2	XM_006713451.4	c.32A>C	p.Tyr11Ser	missense_variant	Exon 2 of 7		XP_006713514.1
NR1D2	NM_001145425.2	c.-194A>C		5_prime_UTR_variant	Exon 2 of 8		NP_001138897.1
NR1D2	NR_110524.2	n.325A>C		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1D2	ENST00000312521.9	c.32A>C	p.Tyr11Ser	missense_variant	Exon 2 of 8	1	NM_005126.5	ENSP00000310006.3
NR1D2	ENST00000383773.8	n.32A>C		non_coding_transcript_exon_variant	Exon 2 of 9	1		ENSP00000373283.3
NR1D2	ENST00000492552.5	n.149A>C		non_coding_transcript_exon_variant	Exon 2 of 8	2		ENSP00000520893.1
NR1D2	ENST00000468700.1	n.-74A>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32A>C (p.Y11S) alteration is located in exon 2 (coding exon 2) of the NR1D2 gene. This alteration results from a A to C substitution at nucleotide position 32, causing the tyrosine (Y) at amino acid position 11 to be replaced by a serine (S). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.55	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.80
MutPred		0.42		Loss of stability (P = 0.0291);
MVP		0.96
MPC		0.84
ClinPred		0.95	D
GERP RS		4.7
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs750368358; hg19: chr3-23996043;