Genetic Variant NM_021975.4:c.329T>C (chr11-65661693-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_021975.4(RELA):c.329T>C(p.Ile110Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I110M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RELA
NM_021975.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.97

Publications

1 publications found

Variant links:

Genes affected

RELA (HGNC:9955): (RELA proto-oncogene, NF-kB subunit) NF-kappa-B is a ubiquitous transcription factor involved in several biological processes. It is held in the cytoplasm in an inactive state by specific inhibitors. Upon degradation of the inhibitor, NF-kappa-B moves to the nucleus and activates transcription of specific genes. NF-kappa-B is composed of NFKB1 or NFKB2 bound to either REL, RELA, or RELB. The most abundant form of NF-kappa-B is NFKB1 complexed with the product of this gene, RELA. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RELA Gene-Disease associations (from GenCC):

combined immunodeficiency due to RELA haploinsufficiency
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
mucocutaneous ulceration, chronic
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hereditary pediatric Behçet-like disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RELA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-65661693-A-G is Pathogenic according to our data. Variant chr11-65661693-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208401.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RELA	NM_021975.4 link	c.329T>C	p.Ile110Thr	missense_variant	Exon 4 of 11	ENST00000406246.8	NP_068810.3	Q04206-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RELA	ENST00000406246.8 link	c.329T>C	p.Ile110Thr	missense_variant	Exon 4 of 11	1	NM_021975.4	ENSP00000384273.3		Q04206-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1438452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713322

African (AFR)

AF:

0.00

AC:

AN:

32948

American (AMR)

AF:

0.00

AC:

AN:

42212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24482

East Asian (EAS)

AF:

0.00

AC:

AN:

39422

South Asian (SAS)

AF:

0.00

AC:

AN:

83004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098878

Other (OTH)

AF:

0.00

AC:

AN:

59396

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Childhood-onset schizophrenia

Pathogenic:1

Jan 01, 2014

Dr. Guy Rouleau's laboratory, McGill University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

COS with Asperger's Disorder -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T;T;T;.;T;.;T;.;.;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.46

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.24

N;.;.;.;N;.;.;.;.;.;.

PhyloP100

7.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.2

N;.;.;N;N;N;N;N;N;N;N

REVEL

Benign

0.28

Sift

Benign

0.57

T;.;.;T;T;T;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;.;.;.;.;.;.

Polyphen

0.88

P;.;.;B;P;.;.;.;.;.;.

Vest4

0.30

MutPred

0.63

Loss of stability (P = 0.0322);Loss of stability (P = 0.0322);Loss of stability (P = 0.0322);Loss of stability (P = 0.0322);Loss of stability (P = 0.0322);.;.;.;Loss of stability (P = 0.0322);.;.;

MVP

0.66

MPC

2.4

ClinPred

0.95

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.51

Mutation Taster

=36/64

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over