1-61406543-GCCCCCCCC-GCCCCCCCCCC

Variant names:

• chr1-61406543-G-GCC
• rs58081092
• NM_001134673.4:c.1255-6_1255-5dupCC

Variant summary

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

The NM_001134673.4(NFIA):​c.1255-6_1255-5dupCC 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 0.0017 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: NFIA NM_001134673.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.886
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 109 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134673.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIA	NM_001134673.4	MANE Select	c.1255-6_1255-5dupCC		splice_region intron	N/A	NP_001128145.1	Q12857-1
	NFIA	NM_001145512.2		c.1390-6_1390-5dupCC		splice_region intron	N/A	NP_001138984.1	Q12857-4
	NFIA	NM_001145511.2		c.1231-6_1231-5dupCC		splice_region intron	N/A	NP_001138983.1	Q12857-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIA	ENST00000403491.8	TSL:1 MANE Select	c.1255-19_1255-18insCC		intron	N/A	ENSP00000384523.3	Q12857-1
	NFIA	ENST00000371187.7	TSL:1	c.1255-19_1255-18insCC		intron	N/A	ENSP00000360229.3	Q12857-2
	NFIA	ENST00000371189.8	TSL:2	c.1390-19_1390-18insCC		intron	N/A	ENSP00000360231.3	Q12857-4

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 109 AN: 63774 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00217

Gnomad AMR AF: 0.00104

Gnomad ASJ AF: 0.000559

Gnomad EAS AF: 0.00138

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00243

Gnomad OTH AF: 0.00122

GnomAD2 exomes AF: 0.0000904 AC: 5 AN: 55298 AF XY: 0.000131

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000146

Gnomad NFE exome AF: 0.0000850

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000695 AC: 565 AN: 813270 Hom.: 1 Cov.: 0 AF XY: 0.000727 AC XY: 296 AN XY: 407028

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

African (AFR) AF: 0.000539 AC: 10 AN: 18538

American (AMR) AF: 0.000580 AC: 12 AN: 20696

Ashkenazi Jewish (ASJ) AF: 0.000510 AC: 7 AN: 13714

East Asian (EAS) AF: 0.00146 AC: 29 AN: 19840

South Asian (SAS) AF: 0.000752 AC: 36 AN: 47848

European-Finnish (FIN) AF: 0.000684 AC: 23 AN: 33626

Middle Eastern (MID) AF: 0.000637 AC: 2 AN: 3142

European-Non Finnish (NFE) AF: 0.000671 AC: 418 AN: 623374

Other (OTH) AF: 0.000862 AC: 28 AN: 32492

⚠️ 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.

GnomAD4 genome AF: 0.00171 AC: 109 AN: 63808 Hom.: 1 Cov.: 0 AF XY: 0.00174 AC XY: 52 AN XY: 29812

African (AFR) AF: 0.00110 AC: 21 AN: 19096

American (AMR) AF: 0.00104 AC: 5 AN: 4792

Ashkenazi Jewish (ASJ) AF: 0.000559 AC: 1 AN: 1788

East Asian (EAS) AF: 0.00138 AC: 3 AN: 2172

South Asian (SAS) AF: 0.00 AC: 0 AN: 1358

European-Finnish (FIN) AF: 0.00107 AC: 3 AN: 2800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.00243 AC: 74 AN: 30424

Other (OTH) AF: 0.00121 AC: 1 AN: 824

Alfa AF: 0.000466 Hom.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.89
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs58081092; hg19: chr1-61872215;