Genetic Variant NFIC:p.Val184Leu (chr19-3382231-G-C) – 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.550G>C(p.Val184Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,601,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

NFIC
NM_001245002.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.18

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=0.018574387).

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIC	NM_001245002.2 link	c.550G>C	p.Val184Leu	missense_variant	Exon 2 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.550G>C	p.Val184Leu	missense_variant	Exon 2 of 11	2	NM_001245002.2	ENSP00000396843.2		P08651-1

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000260

AC:

AN:

238668

Hom.:

AF XY:

0.000238

AC XY:

AN XY:

130222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00464

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.000499

GnomAD4 exome

AF:

0.000164

AC:

237

AN:

1449474

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

107

AN XY:

721266

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00495

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000232

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.000365

GnomAD4 genome

AF:

0.000315

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000814

Hom.:

Bravo

AF:

0.000174

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000353

AC:

ExAC

AF:

0.000207

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.523G>C (p.V175L) alteration is located in exon 1 (coding exon 1) of the NFIC gene. This alteration results from a G to C substitution at nucleotide position 523, causing the valine (V) at amino acid position 175 to be replaced by a leucine (L). 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

0.30

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

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

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.019

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

.;.;.;.;M;M;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.4

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

REVEL

Benign

0.15

Sift

Benign

0.091

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

Sift4G

Benign

0.18

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

Polyphen

0.068, 0.54, 0.40, 0.036

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

Vest4

0.53, 0.48, 0.52, 0.51, 0.64, 0.51

MutPred

0.50

.;.;.;.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.62

MPC

0.50

ClinPred

0.094

GERP RS

1.4

Varity_R

0.028

gMVP

0.92

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