1-61406543-GCCCCCCCC-GCCCCC

Variant names:

• chr1-61406543-GCCC-G
• rs58081092
• NM_001134673.4:c.1255-7_1255-5delCCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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: 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.

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.1255-7_1255-5delCCC		splice_region intron	N/A	NP_001128145.1	Q12857-1
	NFIA	NM_001145512.2		c.1390-7_1390-5delCCC		splice_region intron	N/A	NP_001138984.1	Q12857-4
	NFIA	NM_001145511.2		c.1231-7_1231-5delCCC		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.1255-18_1255-16delCCC		intron	N/A	ENSP00000384523.3	Q12857-1
	NFIA	ENST00000371187.7	TSL:1	c.1255-18_1255-16delCCC		intron	N/A	ENSP00000360229.3	Q12857-2
	NFIA	ENST00000371189.8	TSL:2	c.1390-18_1390-16delCCC		intron	N/A	ENSP00000360231.3	Q12857-4

Frequencies

GnomAD3 genomes AF: 0.00860 AC: 549 AN: 63834 Hom.: 29 Cov.: 0

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

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.: 73 AF XY: 0.00772 AC XY: 3120 AN XY: 404264

⚠️ 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: 94 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: 24 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.

GnomAD4 genome AF: 0.00863 AC: 551 AN: 63870 Hom.: 29 Cov.: 0 AF XY: 0.00814 AC XY: 243 AN XY: 29850

African (AFR) AF: 0.0262 AC: 502 AN: 19124

American (AMR) AF: 0.00292 AC: 14 AN: 4794

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1788

East Asian (EAS) AF: 0.00 AC: 0 AN: 2174

South Asian (SAS) AF: 0.00368 AC: 5 AN: 1358

European-Finnish (FIN) AF: 0.000715 AC: 2 AN: 2798

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

European-Non Finnish (NFE) AF: 0.000788 AC: 24 AN: 30456

Other (OTH) AF: 0.00485 AC: 4 AN: 824

Alfa AF: 0.00 Hom.: 12

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	NFIA-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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

Other links and lift over

dbSNP: rs58081092; hg19: chr1-61872215; COSMIC: COSV63610086; COSMIC: COSV63610086;