1-61406543-GCCCCCCCC-GCCCCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001134673.4(NFIA):c.1255-7_1255-5delCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00751 in 872,130 control chromosomes in the GnomAD database, including 102 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0086 ( 29 hom., cov: 0)

Exomes 𝑓: 0.0074 ( 73 hom. )

Consequence

NFIA
NM_001134673.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.886

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

brain malformations with or without urinary tract defects
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
chromosome 1p32-p31 deletion syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Illumina, Ambry Genetics

NFIA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 1-61406543-GCCC-G is Benign according to our data. Variant chr1-61406543-GCCC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1219266.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00863 (551/63870) while in subpopulation AFR AF = 0.0262 (502/19124). AF 95% confidence interval is 0.0244. There are 29 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 551 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NFIA	NM_001134673.4 link	c.1255-7_1255-5delCCC	splice_region_variant, intron_variant	Intron 8 of 10	ENST00000403491.8	NP_001128145.1	Q12857-1
NFIA	NM_001145512.2 link	c.1390-7_1390-5delCCC	splice_region_variant, intron_variant	Intron 9 of 11		NP_001138984.1	Q12857-4
NFIA	NM_001145511.2 link	c.1231-7_1231-5delCCC	splice_region_variant, intron_variant	Intron 8 of 10		NP_001138983.1	Q12857-3
NFIA	NM_005595.5 link	c.1255-7_1255-5delCCC	splice_region_variant, intron_variant	Intron 8 of 9		NP_005586.1	Q12857-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIA	ENST00000403491.8 link	c.1255-18_1255-16delCCC		intron_variant	Intron 8 of 10	1	NM_001134673.4	ENSP00000384523.3		Q12857-1

Frequencies

GnomAD3 genomes

AF:

0.00860

AC:

549

AN:

63834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0262

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00292

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.000715

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000788

Gnomad OTH

AF:

0.00489

GnomAD2 exomes

AF:

0.0229

AC:

1264

AN:

55298

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.0630

Gnomad AMR exome

AF:

0.0358

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.0193

Gnomad FIN exome

AF:

0.00862

Gnomad NFE exome

AF:

0.0166

Gnomad OTH exome

AF:

0.0172

GnomAD4 exome

AF:

0.00743

AC:

6002

AN:

808260

Hom.:

AF XY:

0.00772

AC XY:

3120

AN XY:

404264

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0404

AC:

745

AN:

18424

American (AMR)

AF:

0.0178

AC:

364

AN:

20436

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

13608

East Asian (EAS)

AF:

0.00526

AC:

104

AN:

19754

South Asian (SAS)

AF:

0.00928

AC:

439

AN:

47306

European-Finnish (FIN)

AF:

0.00488

AC:

162

AN:

33208

Middle Eastern (MID)

AF:

0.00768

AC:

AN:

3124

European-Non Finnish (NFE)

AF:

0.00609

AC:

3779

AN:

620106

Other (OTH)

AF:

0.00901

AC:

291

AN:

32294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.357

Heterozygous variant carriers

379

757

1136

1514

1893

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00863

AC:

551

AN:

63870

Hom.:

Cov.:

AF XY:

0.00814

AC XY:

243

AN XY:

29850

show subpopulations

African (AFR)

AF:

0.0262

AC:

502

AN:

19124

American (AMR)

AF:

0.00292

AC:

AN:

4794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1788

East Asian (EAS)

AF:

0.00

AC:

AN:

2174

South Asian (SAS)

AF:

0.00368

AC:

AN:

1358

European-Finnish (FIN)

AF:

0.000715

AC:

AN:

2798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000788

AC:

AN:

30456

Other (OTH)

AF:

0.00485

AC:

AN:

824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.662

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NFIA-related disorder

Benign:1

Jul 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.89

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over