chr4-102607660-T-G

Position:

• chr4-102607660-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003998.4(NFKB1):​c.2136T>G​(p.His712Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,614,082 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. H712H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0078 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (12 hom.)
• Consequence: NFKB1 NM_003998.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.52

Genes affected

NFKB1 (HGNC:7794): (nuclear factor kappa B subunit 1) This gene encodes a 105 kD protein which can undergo cotranslational processing by the 26S proteasome to produce a 50 kD protein. The 105 kD protein is a Rel protein-specific transcription inhibitor and the 50 kD protein is a DNA binding subunit of the NF-kappa-B (NFKB) protein complex. NFKB is a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth. NFKB is a critical regulator of the immediate-early response to viral infection. Alternative splicing results in multiple transcript variants encoding different isoforms, at least one of which is proteolytically processed. [provided by RefSeq, Aug 2020]

LOC105377347 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFKB1. . Gene score misZ 3.1933 (greater than the threshold 3.09). Trascript score misZ 3.9653 (greater than threshold 3.09). GenCC has associacion of gene with immunodeficiency, common variable, 12, common variable immunodeficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0038932562).
• BP6: Variant 4-102607660-T-G is Benign according to our data. Variant chr4-102607660-T-G is described in ClinVar as [Benign]. Clinvar id is 787033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0078 (1188/152270) while in subpopulation AFR AF= 0.0276 (1146/41536). AF 95% confidence interval is 0.0263. There are 20 homozygotes in gnomad4. There are 609 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFKB1	NM_003998.4	c.2136T>G	p.His712Gln	missense_variant	19/24	ENST00000226574.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFKB1	ENST00000226574.9	c.2136T>G	p.His712Gln	missense_variant	19/24	1	NM_003998.4	P4

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1166 AN: 152152 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00172 AC: 433 AN: 251354 Hom.: 4 AF XY: 0.00127 AC XY: 172 AN XY: 135826

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000780 AC: 1140 AN: 1461812 Hom.: 12 Cov.: 31 AF XY: 0.000659 AC XY: 479 AN XY: 727208

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00780 AC: 1188 AN: 152270 Hom.: 20 Cov.: 32 AF XY: 0.00818 AC XY: 609 AN XY: 74454

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00133 Hom.: 5

Bravo AF: 0.00897

ESP6500AA AF: 0.0184 AC: 81

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.067
DANN	Benign	0.93
DEOGEN2	Benign	0.088	.;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.60	T;.;T;T
MetaRNN	Benign	0.0039	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	.;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.55	N;N;N;.
REVEL	Benign	0.028
Sift	Benign	0.080	T;T;T;.
Sift4G	Benign	0.065	T;T;T;T
Polyphen		0.10	B;B;B;.
Vest4		0.10
MutPred		0.26		.;Loss of disorder (P = 0.1871);Loss of disorder (P = 0.1871);.;
MVP		0.35
MPC		0.39
ClinPred		0.0063	T
GERP RS		-6.4
Varity_R		0.039
gMVP		0.48

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: rs4648099; hg19: chr4-103528817;