1-61082814-C-G

Position:

chr1-61082814-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1PP2BP4_StrongBP6_ModerateBS2

The NM_001134673.4(NFIA):c.23C>G(p.Thr8Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000381 in 1,550,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000039 ( 1 hom. )

Consequence

NFIA
NM_001134673.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.19

Variant links:

Genes affected

NFIA (HGNC:7784): (nuclear factor I A) This gene encodes a member of the NF1 (nuclear factor 1) family of transcription factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

NFIA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a DNA_binding_region CTF/NF-I (size 193) in uniprot entity NFIA_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_001134673.4

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFIA. . Gene score misZ 3.231 (greater than the threshold 3.09). Trascript score misZ 3.6197 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 1p32-p31 deletion syndrome, brain malformations with or without urinary tract defects.

BP4

Computational evidence support a benign effect (MetaRNN=0.05380228).

BP6

Variant 1-61082814-C-G is Benign according to our data. Variant chr1-61082814-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3197468.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NFIA	NM_001134673.4 linkuse as main transcript	c.23C>G	p.Thr8Ser	missense_variant	1/11	ENST00000403491.8
NFIA	NM_001145512.2 linkuse as main transcript	c.158C>G	p.Thr53Ser	missense_variant	2/12
NFIA	NM_005595.5 linkuse as main transcript	c.23C>G	p.Thr8Ser	missense_variant	1/10
NFIA	NM_001145511.2 linkuse as main transcript	c.3+5186C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIA	ENST00000403491.8 linkuse as main transcript	c.23C>G	p.Thr8Ser	missense_variant	1/11	1	NM_001134673.4	P1	Q12857-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

153598

Hom.:

AF XY:

0.000210

AC XY:

AN XY:

80986

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000393

AC:

AN:

1398586

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

689934

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000682

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.16

.;T;.;.;.;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.093

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.68

T;T;T;T;T;T

M_CAP

Uncertain

0.097

MetaRNN

Benign

0.054

T;T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.55

.;N;N;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.1

N;N;N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.19

T;T;T;T;T;T

Sift4G

Benign

0.44

T;T;T;T;T;T

Polyphen

0.011, 0.023

.;B;B;.;.;.

Vest4

0.44

MutPred

0.49

.;Gain of disorder (P = 0.023);Gain of disorder (P = 0.023);Gain of disorder (P = 0.023);Gain of disorder (P = 0.023);Gain of disorder (P = 0.023);

MVP

0.35

MPC

0.75

ClinPred

0.22

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.068

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