rs34631763

chr1-92483381-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005263.5(GFI1):c.107G>A(p.Ser36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,602,830 control chromosomes in the GnomAD database, including 2,489 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S36L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.040 (183 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2306 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 2.50

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018077791).
• BP6: Variant 1-92483381-C-T is Benign according to our data. Variant chr1-92483381-C-T is described in ClinVar as [Benign]. Clinvar id is 259699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92483381-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.107G>A	p.Ser36Asn	missense_variant	2/7	ENST00000294702.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1	ENST00000294702.6	c.107G>A	p.Ser36Asn	missense_variant	2/7	2	NM_005263.5	P1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6151 AN: 152242 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0592

Gnomad OTH AF: 0.0431

GnomAD3 exomes AF: 0.0397 AC: 9753 AN: 245864 Hom.: 261 AF XY: 0.0394 AC XY: 5267 AN XY: 133580

Gnomad AFR exome AF: 0.00945

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00890

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0564

Gnomad OTH exome AF: 0.0456

GnomAD4 exome AF: 0.0521 AC: 75620 AN: 1450470 Hom.: 2306 Cov.: 29 AF XY: 0.0512 AC XY: 36943 AN XY: 722128

Gnomad4 AFR exome AF: 0.00743

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0697

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00977

Gnomad4 FIN exome AF: 0.0559

Gnomad4 NFE exome AF: 0.0593

Gnomad4 OTH exome AF: 0.0500

GnomAD4 genome AF: 0.0404 AC: 6151 AN: 152360 Hom.: 183 Cov.: 33 AF XY: 0.0407 AC XY: 3030 AN XY: 74508

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.0429

Gnomad4 ASJ AF: 0.0651

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0592

Gnomad4 OTH AF: 0.0426

Alfa AF: 0.0545 Hom.: 389

Bravo AF: 0.0369

TwinsUK AF: 0.0663 AC: 246

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0545 AC: 469

ExAC AF: 0.0377 AC: 4572

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0552

EpiControl AF: 0.0552

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with congenital neutropaenia -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0087
FATHMM_MKL	Uncertain	0.90	D
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.50	T;T;T
Polyphen		0.026	B;B;B
Vest4		0.046
MPC		0.60
ClinPred		0.015	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.062

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: rs34631763; hg19: chr1-92948938; COSMIC: COSV54042707;