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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001134673.4(NFIA):c.1255-8_1255-5dupCCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000032 ( 0 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIA	ENST00000403491.8 link	c.1255-19_1255-18insCCCC		intron_variant	Intron 8 of 10	1	NM_001134673.4	ENSP00000384523.3

Frequencies

GnomAD3 genomes

AF:

0.000141

AC:

AN:

63832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000209

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000357

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000320

AC:

AN:

813516

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

407158

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

18556

American (AMR)

AF:

0.0000483

AC:

AN:

20702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13724

East Asian (EAS)

AF:

0.00

AC:

AN:

19860

South Asian (SAS)

AF:

0.0000627

AC:

AN:

47852

European-Finnish (FIN)

AF:

0.0000892

AC:

AN:

33636

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3142

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

623538

Other (OTH)

AF:

0.00

AC:

AN:

32506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000109039), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000141

AC:

AN:

63866

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

29850

show subpopulations

African (AFR)

AF:

0.000105

AC:

AN:

19118

American (AMR)

AF:

0.000209

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:

0.00

AC:

AN:

1358

European-Finnish (FIN)

AF:

0.000357

AC:

AN:

2800

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

30456

Other (OTH)

AF:

0.00

AC:

AN:

824

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.89

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over