4-102607660-T-G

Variant names:

• chr4-102607660-T-G
• rs4648099
• NM_003998.4:c.2136T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H712R) has been classified as Uncertain significance.

• 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:3
• Conservation: PhyloP100: -2.52
• Publications: 11 publications found

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]

NFKB1 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 12

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000304360 (HGNC:58861):

LOC105377347 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1188 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	NM_003998.4	MANE Select	c.2136T>G	p.His712Gln	missense	Exon 19 of 24	NP_003989.2
	NFKB1	NM_001382625.1		c.2136T>G	p.His712Gln	missense	Exon 20 of 25	NP_001369554.1
	NFKB1	NM_001382626.1		c.2136T>G	p.His712Gln	missense	Exon 20 of 25	NP_001369555.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFKB1	ENST00000226574.9	TSL:1 MANE Select	c.2136T>G	p.His712Gln	missense	Exon 19 of 24	ENSP00000226574.4
	NFKB1	ENST00000394820.8	TSL:1	c.2133T>G	p.His711Gln	missense	Exon 19 of 24	ENSP00000378297.4
	NFKB1	ENST00000505458.5	TSL:1	c.2133T>G	p.His711Gln	missense	Exon 19 of 24	ENSP00000424790.1

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

GnomAD2 exomes AF: 0.00172 AC: 433 AN: 251354 AF XY: 0.00127

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 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

African (AFR) AF: 0.0282 AC: 945 AN: 33472

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111972

Other (OTH) AF: 0.00182 AC: 110 AN: 60396

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

African (AFR) AF: 0.0276 AC: 1146 AN: 41536

American (AMR) AF: 0.00189 AC: 29 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68010

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00191 Hom.: 10

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Immunodeficiency, common variable, 12 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N
PhyloP100		-2.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.028
Sift	Benign	0.080	T
Sift4G	Benign	0.065	T
Polyphen		0.10	B
Vest4		0.10
MutPred		0.26		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
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs4648099; hg19: chr4-103528817;