1-61406543-GCCCCCCCC-GCCCCCCCCC

Variant names:

• chr1-61406543-G-GC
• rs58081092
• NM_001134673.4:c.1255-5dupC

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.1255-5dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (46 hom., cov: 0)
  • Exomes 𝑓: 0.0066 (2 hom.)
• Consequence: NFIA NM_001134673.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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-G-GC is Benign according to our data. Variant chr1-61406543-G-GC is described in ClinVar as Likely_benign. ClinVar VariationId is 2638855.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0208 (1325/63654) while in subpopulation NFE AF = 0.0253 (768/30376). AF 95% confidence interval is 0.0238. There are 46 homozygotes in GnomAd4. There are 590 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1325 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIA	NM_001134673.4	c.1255-5dupC		splice_region_variant, intron_variant	Intron 8 of 10	ENST00000403491.8	NP_001128145.1
NFIA	NM_001145512.2	c.1390-5dupC		splice_region_variant, intron_variant	Intron 9 of 11		NP_001138984.1
NFIA	NM_001145511.2	c.1231-5dupC		splice_region_variant, intron_variant	Intron 8 of 10		NP_001138983.1
NFIA	NM_005595.5	c.1255-5dupC		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.1255-19_1255-18insC		intron_variant	Intron 8 of 10	1	NM_001134673.4	ENSP00000384523.3

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 1326 AN: 63620 Hom.: 46 Cov.: 0

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.0240

Gnomad AMR AF: 0.0180

Gnomad ASJ AF: 0.0292

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.0189

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0102

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0284

GnomAD2 exomes AF: 0.00184 AC: 102 AN: 55298 AF XY: 0.00174

Gnomad AFR exome AF: 0.000568

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000679

Gnomad FIN exome AF: 0.000877

Gnomad NFE exome AF: 0.00119

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00658 AC: 5347 AN: 813002 Hom.: 2 Cov.: 0 AF XY: 0.00692 AC XY: 2816 AN XY: 406884

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

African (AFR) AF: 0.00525 AC: 97 AN: 18484

American (AMR) AF: 0.00696 AC: 144 AN: 20692

Ashkenazi Jewish (ASJ) AF: 0.0103 AC: 141 AN: 13718

East Asian (EAS) AF: 0.00887 AC: 176 AN: 19836

South Asian (SAS) AF: 0.00860 AC: 411 AN: 47800

European-Finnish (FIN) AF: 0.00717 AC: 241 AN: 33624

Middle Eastern (MID) AF: 0.00541 AC: 17 AN: 3140

European-Non Finnish (NFE) AF: 0.00620 AC: 3866 AN: 623242

Other (OTH) AF: 0.00782 AC: 254 AN: 32466

⚠️ 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: 0.0208 AC: 1325 AN: 63654 Hom.: 46 Cov.: 0 AF XY: 0.0198 AC XY: 590 AN XY: 29758

African (AFR) AF: 0.0153 AC: 292 AN: 19026

American (AMR) AF: 0.0180 AC: 86 AN: 4782

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 52 AN: 1782

East Asian (EAS) AF: 0.0143 AC: 31 AN: 2172

South Asian (SAS) AF: 0.0184 AC: 25 AN: 1358

European-Finnish (FIN) AF: 0.0129 AC: 36 AN: 2790

Middle Eastern (MID) AF: 0.0106 AC: 1 AN: 94

European-Non Finnish (NFE) AF: 0.0253 AC: 768 AN: 30376

Other (OTH) AF: 0.0282 AC: 23 AN: 816

Alfa AF: 0.00308 Hom.: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NFIA: PM2, BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;