chr1-92480615-T-A

Variant names:

• chr1-92480615-T-A
• rs755193129
• NM_005263.5:c.772A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000294702.6(GFI1):​c.772A>T​(p.Ile258Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I258V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GFI1 ENST00000294702.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neutropenia, severe congenital, 2, autosomal dominant

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• severe congenital neutropenia

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• autosomal dominant severe congenital neutropenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4041975).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000294702.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	NM_005263.5	MANE Select	c.772A>T	p.Ile258Phe	missense	Exon 4 of 7	NP_005254.2
	GFI1	NM_001127215.3		c.772A>T	p.Ile258Phe	missense	Exon 4 of 7	NP_001120687.1
	GFI1	NM_001127216.3		c.772A>T	p.Ile258Phe	missense	Exon 4 of 7	NP_001120688.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	ENST00000294702.6	TSL:2 MANE Select	c.772A>T	p.Ile258Phe	missense	Exon 4 of 7	ENSP00000294702.5
	GFI1	ENST00000370332.5	TSL:1	c.772A>T	p.Ile258Phe	missense	Exon 4 of 7	ENSP00000359357.1
	GFI1	ENST00000427103.6	TSL:1	c.772A>T	p.Ile258Phe	missense	Exon 4 of 7	ENSP00000399719.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412602 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 699706

African (AFR) AF: 0.00 AC: 0 AN: 32734

American (AMR) AF: 0.00 AC: 0 AN: 39704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25302

East Asian (EAS) AF: 0.00 AC: 0 AN: 37888

South Asian (SAS) AF: 0.00 AC: 0 AN: 81230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.15e-7 AC: 1 AN: 1092412

Other (OTH) AF: 0.00 AC: 0 AN: 58798

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Benign	0.78
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.0026
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.27
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.12
Sift	Benign	0.034	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.87	P
Vest4		0.24
MutPred		0.23		Gain of disorder (P = 0.1109)
MVP		0.73
MPC		1.9
ClinPred		0.86	D
GERP RS		4.0
Varity_R		0.21
gMVP		0.43
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs755193129; hg19: chr1-92946172;