9-91409346-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_005384.3(NFIL3):c.1389A>G(p.Ter463=) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000654 in 1,552,854 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (11 hom.)
• Consequence: NFIL3 NM_005384.3 stop_retained
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.49

Genes affected

NFIL3 (HGNC:7787): (nuclear factor, interleukin 3 regulated) The protein encoded by this gene is a transcriptional regulator that binds as a homodimer to activating transcription factor (ATF) sites in many cellular and viral promoters. The encoded protein represses PER1 and PER2 expression and therefore plays a role in the regulation of circadian rhythm. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-91409346-T-C is Benign according to our data. Variant chr9-91409346-T-C is described in ClinVar as [Benign]. Clinvar id is 721540.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000939 (143/152348) while in subpopulation EAS AF= 0.0222 (115/5190). AF 95% confidence interval is 0.0189. There are 2 homozygotes in gnomad4. There are 86 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 145 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIL3	NM_005384.3	c.1389A>G	p.Ter463=	stop_retained_variant	2/2	ENST00000297689.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIL3	ENST00000297689.4	c.1389A>G	p.Ter463=	stop_retained_variant	2/2	1	NM_005384.3	P1

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152230 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00224 AC: 454 AN: 202988 Hom.: 6 AF XY: 0.00205 AC XY: 222 AN XY: 108404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.000176

Gnomad EAS exome AF: 0.0232

Gnomad SAS exome AF: 0.000102

Gnomad FIN exome AF: 0.000636

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00296

GnomAD4 exome AF: 0.000623 AC: 873 AN: 1400506 Hom.: 11 Cov.: 30 AF XY: 0.000597 AC XY: 413 AN XY: 691226

Gnomad4 AFR exome AF: 0.0000322

Gnomad4 AMR exome AF: 0.000149

Gnomad4 ASJ exome AF: 0.000227

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.000225

Gnomad4 FIN exome AF: 0.000760

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00115 AC XY: 86 AN XY: 74504

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0222

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.000899

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	9.0
Dann	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs3747840; hg19: chr9-94171628;