Genetic Variant NM_001134673.4:c.1255-8_1255-5delCCCC (chr1-61406543-GCCCC-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001134673.4(NFIA):c.1255-8_1255-5delCCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 875,344 control chromosomes in the GnomAD database, including 1 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

NFIA
NM_001134673.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NFIA	NM_001134673.4 link	c.1255-8_1255-5delCCCC	splice_region_variant, intron_variant	Intron 8 of 10	ENST00000403491.8	NP_001128145.1	Q12857-1
NFIA	NM_001145512.2 link	c.1390-8_1390-5delCCCC	splice_region_variant, intron_variant	Intron 9 of 11		NP_001138984.1	Q12857-4
NFIA	NM_001145511.2 link	c.1231-8_1231-5delCCCC	splice_region_variant, intron_variant	Intron 8 of 10		NP_001138983.1	Q12857-3
NFIA	NM_005595.5 link	c.1255-8_1255-5delCCCC	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_1255-15delCCCC		intron_variant	Intron 8 of 10	1	NM_001134673.4	ENSP00000384523.3		Q12857-1

Frequencies

GnomAD3 genomes

AF:

0.0000157

AC:

AN:

63834

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000328

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00127

AC:

AN:

55298

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.00170

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.00135

Gnomad EAS exome

AF:

0.00102

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00111

AC:

898

AN:

811510

Hom.:

AF XY:

0.00115

AC XY:

467

AN XY:

406102

show subpopulations

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

African (AFR)

AF:

0.00222

AC:

AN:

18510

American (AMR)

AF:

0.00111

AC:

AN:

20628

Ashkenazi Jewish (ASJ)

AF:

0.000950

AC:

AN:

13684

East Asian (EAS)

AF:

0.000504

AC:

AN:

19826

South Asian (SAS)

AF:

0.00130

AC:

AN:

47734

European-Finnish (FIN)

AF:

0.000387

AC:

AN:

33586

Middle Eastern (MID)

AF:

0.000318

AC:

AN:

3140

European-Non Finnish (NFE)

AF:

0.00112

AC:

699

AN:

621952

Other (OTH)

AF:

0.00111

AC:

AN:

32450

⚠️ 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: 0.275

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.0000157

AC:

AN:

63834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

29818

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19060

American (AMR)

AF:

0.00

AC:

AN:

4796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1788

East Asian (EAS)

AF:

0.00

AC:

AN:

2180

South Asian (SAS)

AF:

0.00

AC:

AN:

1376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000328

AC:

AN:

30458

Other (OTH)

AF:

0.00

AC:

AN:

818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.89

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over