6-31558135-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005007.4(NFKBIL1):c.670C>T(p.Arg224Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.933 in 1,611,914 control chromosomes in the GnomAD database, including 702,866 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.95 (69357 hom., cov: 31)
  • Exomes 𝑓: 0.93 (633509 hom.)
• Consequence: NFKBIL1 NM_005007.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01

Genes affected

NFKBIL1 (HGNC:7800): (NFKB inhibitor like 1) This gene encodes a divergent member of the I-kappa-B family of proteins. Its function has not been determined. The gene lies within the major histocompatibility complex (MHC) class I region on chromosome 6. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.35233E-7).
• BP6: Variant 6-31558135-C-T is Benign according to our data. Variant chr6-31558135-C-T is described in ClinVar as [Benign]. Clinvar id is 3060091.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKBIL1	NM_005007.4	c.670C>T	p.Arg224Cys	missense_variant	4/4	ENST00000376148.9
NFKBIL1	NM_001144961.2	c.625C>T	p.Arg209Cys	missense_variant	4/4
NFKBIL1	NM_001144962.2	c.601C>T	p.Arg201Cys	missense_variant	4/4
NFKBIL1	NM_001144963.2	c.556C>T	p.Arg186Cys	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKBIL1	ENST00000376148.9	c.670C>T	p.Arg224Cys	missense_variant	4/4	1	NM_005007.4	P4
NFKBIL1	ENST00000376145.8	c.625C>T	p.Arg209Cys	missense_variant	4/4	1
NFKBIL1	ENST00000376146.8	c.601C>T	p.Arg201Cys	missense_variant	4/4	4		A1

Frequencies

GnomAD3 genomes AF: 0.954 AC: 145111 AN: 152130 Hom.: 69294 Cov.: 31

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.975

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.922

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.927

Gnomad OTH AF: 0.971

GnomAD3 exomes AF: 0.955 AC: 231948 AN: 242782 Hom.: 110974 AF XY: 0.956 AC XY: 127023 AN XY: 132808

Gnomad AFR exome AF: 0.987

Gnomad AMR exome AF: 0.976

Gnomad ASJ exome AF: 0.993

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.917

Gnomad NFE exome AF: 0.929

Gnomad OTH exome AF: 0.953

GnomAD4 exome AF: 0.931 AC: 1359001 AN: 1459666 Hom.: 633509 Cov.: 76 AF XY: 0.934 AC XY: 677948 AN XY: 726054

Gnomad4 AFR exome AF: 0.988

Gnomad4 AMR exome AF: 0.976

Gnomad4 ASJ exome AF: 0.993

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.919

Gnomad4 NFE exome AF: 0.918

Gnomad4 OTH exome AF: 0.942

GnomAD4 genome AF: 0.954 AC: 145233 AN: 152248 Hom.: 69357 Cov.: 31 AF XY: 0.955 AC XY: 71064 AN XY: 74426

Gnomad4 AFR AF: 0.986

Gnomad4 AMR AF: 0.967

Gnomad4 ASJ AF: 0.992

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.922

Gnomad4 NFE AF: 0.927

Gnomad4 OTH AF: 0.972

Alfa AF: 0.937 Hom.: 109995

Bravo AF: 0.959

TwinsUK AF: 0.918 AC: 3404

ALSPAC AF: 0.917 AC: 3534

ESP6500AA AF: 0.983 AC: 2966

ESP6500EA AF: 0.929 AC: 5035

ExAC AF: 0.955 AC: 112326

Asia WGS AF: 0.996 AC: 3465 AN: 3478

EpiCase AF: 0.940

EpiControl AF: 0.942

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NFKBIL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.39
Dann	Benign	0.86
DEOGEN2	Benign	0.022	T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.20	T;.;T
MetaRNN	Benign	7.4e-7	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.090
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.041
MPC		0.83
ClinPred		0.0080	T
GERP RS		-8.9
gMVP		0.22

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: rs3130062; hg19: chr6-31525912;