rs80337126

Positions:

• chr1-92478631-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005263.5(GFI1):​c.1047C>T​(p.Phe349Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.0196 in 1,613,968 control chromosomes in the GnomAD database, including 368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 32)
  • Exomes 𝑓: 0.020 (343 hom.)
• Consequence: GFI1 NM_005263.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.92

Genes affected

GFI1 (HGNC:4237): (growth factor independent 1 transcriptional repressor) This gene encodes a nuclear zinc finger protein that functions as a transcriptional repressor. This protein plays a role in diverse developmental contexts, including hematopoiesis and oncogenesis. It functions as part of a complex along with other cofactors to control histone modifications that lead to silencing of the target gene promoters. Mutations in this gene cause autosomal dominant severe congenital neutropenia, and also dominant nonimmune chronic idiopathic neutropenia of adults, which are heterogeneous hematopoietic disorders that cause predispositions to leukemias and infections. Multiple alternatively spliced variants, encoding the same protein, have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-92478631-G-A is Benign according to our data. Variant chr1-92478631-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0132 (2010/152170) while in subpopulation NFE AF= 0.0212 (1442/68004). AF 95% confidence interval is 0.0203. There are 25 homozygotes in gnomad4. There are 960 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2010 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.1047C>T	p.Phe349Phe	synonymous_variant	6/7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.1047C>T	p.Phe349Phe	synonymous_variant	6/7	2	NM_005263.5	ENSP00000294702.5
GFI1	ENST00000370332.5	c.1047C>T	p.Phe349Phe	synonymous_variant	6/7	1		ENSP00000359357.1
GFI1	ENST00000427103.6	c.1047C>T	p.Phe349Phe	synonymous_variant	6/7	1		ENSP00000399719.1
GFI1	ENST00000696667.1	c.138+1717C>T		intron_variant				ENSP00000512792.1

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2011 AN: 152054 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00989

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0137 AC: 3451 AN: 251492 Hom.: 42 AF XY: 0.0140 AC XY: 1906 AN XY: 135920

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00610

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.0173

Gnomad NFE exome AF: 0.0206

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0203 AC: 29670 AN: 1461798 Hom.: 343 Cov.: 33 AF XY: 0.0200 AC XY: 14545 AN XY: 727198

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.00615

Gnomad4 ASJ exome AF: 0.00673

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0132 AC: 2010 AN: 152170 Hom.: 25 Cov.: 32 AF XY: 0.0129 AC XY: 960 AN XY: 74406

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.00988

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0179 Hom.: 17

Bravo AF: 0.0128

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0197

EpiControl AF: 0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GFI1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 11, 2020

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). -

Neutropenia, severe congenital, 2, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.73

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: rs80337126; hg19: chr1-92944188; COSMIC: COSV54042177; COSMIC: COSV54042177;