3-23959738-C-T

Variant names:

• chr3-23959738-C-T
• NM_005126.5:c.440C>T

Variant summary

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

The NM_005126.5(NR1D2):​c.440C>T​(p.Ser147Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NR1D2 NM_005126.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1D2	NM_005126.5	c.440C>T	p.Ser147Phe	missense_variant	Exon 4 of 8	ENST00000312521.9	NP_005117.3
NR1D2	NM_001145425.2	c.215C>T	p.Ser72Phe	missense_variant	Exon 4 of 8		NP_001138897.1
NR1D2	XM_006713451.4	c.440C>T	p.Ser147Phe	missense_variant	Exon 4 of 7		XP_006713514.1
NR1D2	NR_110524.2	n.733C>T		non_coding_transcript_exon_variant	Exon 4 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1D2	ENST00000312521.9	c.440C>T	p.Ser147Phe	missense_variant	Exon 4 of 8	1	NM_005126.5	ENSP00000310006.3
NR1D2	ENST00000383773.8	n.440C>T		non_coding_transcript_exon_variant	Exon 4 of 9	1		ENSP00000373283.3
NR1D2	ENST00000468700.1	n.335C>T		non_coding_transcript_exon_variant	Exon 3 of 4	3
NR1D2	ENST00000492552.5	n.557C>T		non_coding_transcript_exon_variant	Exon 4 of 8	2		ENSP00000520893.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.440C>T (p.S147F) alteration is located in exon 4 (coding exon 4) of the NR1D2 gene. This alteration results from a C to T substitution at nucleotide position 440, causing the serine (S) at amino acid position 147 to be replaced by a phenylalanine (F). 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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.026	D
Vest4		0.51
MutPred		0.40		Loss of disorder (P = 0.0325);
MVP		0.67
MPC		0.83
ClinPred		0.96	D
GERP RS		5.0
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-24001229;