rs149914857

chr1-92481068-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005263.5(GFI1):c.319C>G(p.Pro107Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,611,614 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P107P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (13 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.36

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008533537).
• BP6: Variant 1-92481068-G-C is Benign according to our data. Variant chr1-92481068-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 259703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92481068-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFI1	NM_005263.5	c.319C>G	p.Pro107Ala	missense_variant	4/7	ENST00000294702.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFI1	ENST00000294702.6	c.319C>G	p.Pro107Ala	missense_variant	4/7	2	NM_005263.5	P1
GFI1	ENST00000370332.5	c.319C>G	p.Pro107Ala	missense_variant	4/7	1		P1
GFI1	ENST00000427103.6	c.319C>G	p.Pro107Ala	missense_variant	4/7	1		P1

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152208 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00221 AC: 530 AN: 239476 Hom.: 2 AF XY: 0.00230 AC XY: 301 AN XY: 130642

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00225

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000791

Gnomad FIN exome AF: 0.000675

Gnomad NFE exome AF: 0.00328

Gnomad OTH exome AF: 0.00374

GnomAD4 exome AF: 0.00395 AC: 5764 AN: 1459288 Hom.: 13 Cov.: 34 AF XY: 0.00387 AC XY: 2811 AN XY: 726014

Gnomad4 AFR exome AF: 0.000839

Gnomad4 AMR exome AF: 0.00235

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000917

Gnomad4 FIN exome AF: 0.000988

Gnomad4 NFE exome AF: 0.00467

Gnomad4 OTH exome AF: 0.00390

GnomAD4 genome AF: 0.00259 AC: 395 AN: 152326 Hom.: 2 Cov.: 34 AF XY: 0.00247 AC XY: 184 AN XY: 74478

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00343 Hom.: 1

Bravo AF: 0.00241

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00232 AC: 279

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00356

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GFI1: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0085	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.11
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.068	T;T;T
Polyphen		0.0090	B;B;B
Vest4		0.24
MVP		0.79
MPC		1.4
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.087
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149914857; hg19: chr1-92946625;