1-61406543-GCCCCCCCC-GCCCCCC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001134673.4(NFIA):​c.1255-6_1255-5delCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 863,634 control chromosomes in the GnomAD database, including 846 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 0.055 (326 hom., cov: 0)
  • Exomes 𝑓: 0.035 (520 hom.)
• Consequence: NFIA NM_001134673.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts 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 -16 ACMG points.

• BP6: Variant 1-61406543-GCC-G is Benign according to our data. Variant chr1-61406543-GCC-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIA	NM_001134673.4	c.1255-6_1255-5delCC		splice_region_variant, intron_variant	Intron 8 of 10	ENST00000403491.8	NP_001128145.1
NFIA	NM_001145512.2	c.1390-6_1390-5delCC		splice_region_variant, intron_variant	Intron 9 of 11		NP_001138984.1
NFIA	NM_001145511.2	c.1231-6_1231-5delCC		splice_region_variant, intron_variant	Intron 8 of 10		NP_001138983.1
NFIA	NM_005595.5	c.1255-6_1255-5delCC		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_1255-17delCC		intron_variant	Intron 8 of 10	1	NM_001134673.4	ENSP00000384523.3

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 3477 AN: 63764 Hom.: 324 Cov.: 0

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0313

Gnomad ASJ AF: 0.00783

Gnomad EAS AF: 0.00321

Gnomad SAS AF: 0.000727

Gnomad FIN AF: 0.00430

Gnomad MID AF: 0.0306

Gnomad NFE AF: 0.00535

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0748 AC: 4137 AN: 55298 AF XY: 0.0686

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.0631

Gnomad EAS exome AF: 0.0577

Gnomad FIN exome AF: 0.0463

Gnomad NFE exome AF: 0.0523

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0351 AC: 28090 AN: 799836 Hom.: 520 AF XY: 0.0367 AC XY: 14679 AN XY: 399808

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

African (AFR) AF: 0.177 AC: 3224 AN: 18230

American (AMR) AF: 0.0716 AC: 1455 AN: 20310

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 557 AN: 13470

East Asian (EAS) AF: 0.0319 AC: 622 AN: 19494

South Asian (SAS) AF: 0.0470 AC: 2176 AN: 46332

European-Finnish (FIN) AF: 0.0346 AC: 1103 AN: 31854

Middle Eastern (MID) AF: 0.0268 AC: 83 AN: 3102

European-Non Finnish (NFE) AF: 0.0285 AC: 17500 AN: 615078

Other (OTH) AF: 0.0429 AC: 1370 AN: 31966

⚠️ 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: 0.0549 AC: 3501 AN: 63798 Hom.: 326 Cov.: 0 AF XY: 0.0546 AC XY: 1629 AN XY: 29818

African (AFR) AF: 0.163 AC: 3115 AN: 19074

American (AMR) AF: 0.0311 AC: 149 AN: 4792

Ashkenazi Jewish (ASJ) AF: 0.00783 AC: 14 AN: 1788

East Asian (EAS) AF: 0.00322 AC: 7 AN: 2174

South Asian (SAS) AF: 0.000736 AC: 1 AN: 1358

European-Finnish (FIN) AF: 0.00430 AC: 12 AN: 2788

Middle Eastern (MID) AF: 0.0426 AC: 4 AN: 94

European-Non Finnish (NFE) AF: 0.00535 AC: 163 AN: 30446

Other (OTH) AF: 0.0437 AC: 36 AN: 824

Alfa AF: 0.000373 Hom.: 12

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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;