rs143913803

Positions:

• chr1-92482994-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005263.5(GFI1):​c.168C>T​(p.Ser56Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,610,104 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (25 hom.)
• Consequence: GFI1 NM_005263.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.451

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]

GFI1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-92482994-G-A is Benign according to our data. Variant chr1-92482994-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92482994-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.451 with no splicing effect.
• BS2: High AC in GnomAd4 at 535 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.168C>T	p.Ser56Ser	synonymous_variant	3/7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.168C>T	p.Ser56Ser	synonymous_variant	3/7	2	NM_005263.5	ENSP00000294702.5

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 535 AN: 152214 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00634

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00252 AC: 628 AN: 249016 Hom.: 1 AF XY: 0.00234 AC XY: 316 AN XY: 134978

Gnomad AFR exome AF: 0.000625

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00141

Gnomad FIN exome AF: 0.000729

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00498 AC: 7258 AN: 1457772 Hom.: 25 Cov.: 33 AF XY: 0.00484 AC XY: 3505 AN XY: 724658

Gnomad4 AFR exome AF: 0.000869

Gnomad4 AMR exome AF: 0.00278

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.000918

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00351 AC: 535 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74504

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00633

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00350 Hom.: 1

Bravo AF: 0.00388

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 02, 2024	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 24, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GFI1: BP4, BP7, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143913803; hg19: chr1-92948551;