Genetic Variant NFIC:p.Ala189Glu (chr19-3425109-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001245002.2(NFIC):c.566C>A(p.Ala189Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000905 in 1,613,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 1 hom. )

Consequence

NFIC
NM_001245002.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.96

Variant links:

Genes affected

NFIC (HGNC:7786): (nuclear factor I C) The protein encoded by this gene belongs to the CTF/NF-I family. These are dimeric DNA-binding proteins, and function as cellular transcription factors and as replication factors for adenovirus DNA replication. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Oct 2011]

NFIC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017503679).

BS2

High AC in GnomAd4 at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIC	NM_001245002.2 link	c.566C>A	p.Ala189Glu	missense_variant	Exon 3 of 11	ENST00000443272.3	NP_001231931.1	P08651-1B7Z4T6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIC	ENST00000443272.3 link	c.566C>A	p.Ala189Glu	missense_variant	Exon 3 of 11	2	NM_001245002.2	ENSP00000396843.2		P08651-1

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.000716

AC:

178

AN:

248598

Hom.:

AF XY:

0.000721

AC XY:

AN XY:

134574

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000609

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000488

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00181

GnomAD4 exome

AF:

0.000907

AC:

1325

AN:

1460990

Hom.:

Cov.:

AF XY:

0.000909

AC XY:

661

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000694

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.00111

Gnomad4 OTH exome

AF:

0.000696

GnomAD4 genome

AF:

0.000886

AC:

135

AN:

152372

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000813

Hom.:

Bravo

AF:

0.000941

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000585

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 28, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539C>A (p.A180E) alteration is located in exon 1 (coding exon 1) of the NFIC gene. This alteration results from a C to A substitution at nucleotide position 539, causing the alanine (A) at amino acid position 180 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.15

.;.;.;.;.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.018

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;.;.;L;L;L

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

.;.;N;N;.;.

REVEL

Benign

0.13

Sift

Uncertain

0.0050

.;.;D;D;.;.

Sift4G

Benign

0.10

.;T;T;T;T;T

Polyphen

0.050, 0.069, 0.041

.;B;B;B;.;B

Vest4

0.46, 0.46, 0.50, 0.38, 0.45

MVP

0.42

MPC

0.63

ClinPred

0.042

GERP RS

3.3

Varity_R

0.12

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over