1-61406543-GCCCCCCCC-GCCC

Variant names:

• chr1-61406543-GCCCCC-G
• rs58081092
• NM_001134673.4:c.1255-9_1255-5delCCCCC

Variant summary

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

The NM_001134673.4(NFIA):​c.1255-9_1255-5delCCCCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 813,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.00016 (0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIA	NM_001134673.4	c.1255-9_1255-5delCCCCC		splice_region_variant, intron_variant	Intron 8 of 10	ENST00000403491.8	NP_001128145.1
NFIA	NM_001145512.2	c.1390-9_1390-5delCCCCC		splice_region_variant, intron_variant	Intron 9 of 11		NP_001138984.1
NFIA	NM_001145511.2	c.1231-9_1231-5delCCCCC		splice_region_variant, intron_variant	Intron 8 of 10		NP_001138983.1
NFIA	NM_005595.5	c.1255-9_1255-5delCCCCC		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	c.1255-18_1255-14delCCCCC		intron_variant	Intron 8 of 10	1	NM_001134673.4	ENSP00000384523.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.000165 AC: 134 AN: 813072 Hom.: 0 AF XY: 0.000157 AC XY: 64 AN XY: 406944

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

African (AFR) AF: 0.000162 AC: 3 AN: 18548

American (AMR) AF: 0.0000483 AC: 1 AN: 20698

Ashkenazi Jewish (ASJ) AF: 0.0000729 AC: 1 AN: 13718

East Asian (EAS) AF: 0.0000504 AC: 1 AN: 19854

South Asian (SAS) AF: 0.000125 AC: 6 AN: 47844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33634

Middle Eastern (MID) AF: 0.000318 AC: 1 AN: 3142

European-Non Finnish (NFE) AF: 0.000185 AC: 115 AN: 623138

Other (OTH) AF: 0.000185 AC: 6 AN: 32496

⚠️ 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 Cov.: 0

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

Other links and lift over

dbSNP: rs58081092; hg19: chr1-61872215;