1-92475293-G-T

Variant names:

• chr1-92475293-G-T
• rs1325432
• NM_005263.5:c.*736C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005263.5(GFI1):​c.*736C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 152,440 control chromosomes in the GnomAD database, including 2,055 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2047 hom., cov: 31)
  • Exomes 𝑓: 0.15 (8 hom.)
• Consequence: GFI1 NM_005263.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.385
• Publications: 15 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005263.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	NM_005263.5	MANE Select	c.*736C>A		3_prime_UTR	Exon 7 of 7	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.*736C>A		3_prime_UTR	Exon 7 of 7	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.*736C>A		3_prime_UTR	Exon 7 of 7	NP_001120688.1	Q99684

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	ENST00000294702.6	TSL:2 MANE Select	c.*736C>A		3_prime_UTR	Exon 7 of 7	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.*736C>A		3_prime_UTR	Exon 7 of 7	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.*736C>A		3_prime_UTR	Exon 7 of 7	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23645 AN: 151944 Hom.: 2048 Cov.: 31

Gnomad AFR AF: 0.0902

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.154

GnomAD4 exome AF: 0.148 AC: 56 AN: 378 Hom.: 8 Cov.: 0 AF XY: 0.170 AC XY: 32 AN XY: 188

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.268 AC: 15 AN: 56

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.100 AC: 1 AN: 10

European-Finnish (FIN) AF: 0.333 AC: 2 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.123 AC: 36 AN: 292

Other (OTH) AF: 0.167 AC: 2 AN: 12

GnomAD4 genome AF: 0.155 AC: 23641 AN: 152062 Hom.: 2047 Cov.: 31 AF XY: 0.160 AC XY: 11883 AN XY: 74322

African (AFR) AF: 0.0901 AC: 3739 AN: 41496

American (AMR) AF: 0.194 AC: 2973 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3468

East Asian (EAS) AF: 0.156 AC: 805 AN: 5166

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4816

European-Finnish (FIN) AF: 0.179 AC: 1886 AN: 10562

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11692 AN: 67948

Other (OTH) AF: 0.152 AC: 322 AN: 2114

Alfa AF: 0.165 Hom.: 4759

Bravo AF: 0.152

Asia WGS AF: 0.204 AC: 709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.70
DANN	Benign	0.32
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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: rs1325432; hg19: chr1-92940850;