chr6-31558135-C-T

Position:

• chr6-31558135-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
NFKBIL1	NM_005007.4	c.670C>T	p.Arg224Cys	missense_variant	4/4	ENST00000376148.9	NP_004998.3
NFKBIL1	NM_001144961.2	c.625C>T	p.Arg209Cys	missense_variant	4/4		NP_001138433.1
NFKBIL1	NM_001144962.2	c.601C>T	p.Arg201Cys	missense_variant	4/4		NP_001138434.1
NFKBIL1	NM_001144963.2	c.556C>T	p.Arg186Cys	missense_variant	4/4		NP_001138435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFKBIL1	ENST00000376148.9	c.670C>T	p.Arg224Cys	missense_variant	4/4	1	NM_005007.4	ENSP00000365318	P4
NFKBIL1	ENST00000376145.8	c.625C>T	p.Arg209Cys	missense_variant	4/4	1		ENSP00000365315
NFKBIL1	ENST00000376146.8	c.601C>T	p.Arg201Cys	missense_variant	4/4	4		ENSP00000365316	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: no assertion criteria provided

Submissions by phenotype

NFKBIL1-related disorder Benign:1

Benign, no assertion criteria provided

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;