chr1-61406543-GCCC-G

Position:

• chr1-61406543-GCCC-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001134673.4(NFIA):​c.1255-7_1255-5del variant causes a splice polypyrimidine tract, 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. 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_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.886

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]

ACMG classification

Verdict is Benign. Variant got -16 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 id is 1219266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 551 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIA	NM_001134673.4	c.1255-7_1255-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000403491.8
NFIA	NM_001145511.2	c.1231-7_1231-5del		splice_polypyrimidine_tract_variant, intron_variant
NFIA	NM_001145512.2	c.1390-7_1390-5del		splice_polypyrimidine_tract_variant, intron_variant
NFIA	NM_005595.5	c.1255-7_1255-5del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIA	ENST00000403491.8	c.1255-7_1255-5del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001134673.4	P1

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

GnomAD3 exomes AF: 0.0229 AC: 1264 AN: 55298 Hom.: 8 AF XY: 0.0217 AC XY: 661 AN XY: 30448

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 SAS exome AF: 0.0186

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

Gnomad4 AFR exome AF: 0.0404

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.00691

Gnomad4 EAS exome AF: 0.00526

Gnomad4 SAS exome AF: 0.00928

Gnomad4 FIN exome AF: 0.00488

Gnomad4 NFE exome AF: 0.00609

Gnomad4 OTH exome AF: 0.00901

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

Gnomad4 AFR AF: 0.0262

Gnomad4 AMR AF: 0.00292

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00368

Gnomad4 FIN AF: 0.000715

Gnomad4 NFE AF: 0.000788

Gnomad4 OTH AF: 0.00485

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 10, 2019

- -

NFIA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs58081092; hg19: chr1-61872215;