1-92475800-A-G

Position:

• chr1-92475800-A-G

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.*229T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 574,372 control chromosomes in the GnomAD database, including 144,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39187 hom., cov: 31)
  • Exomes 𝑓: 0.70 (105560 hom.)
• Consequence: GFI1 NM_005263.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.95

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 (BayesDel_noAF=-0.9).
• BP6: Variant 1-92475800-A-G is Benign according to our data. Variant chr1-92475800-A-G is described in ClinVar as [Benign]. Clinvar id is 1271213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFI1	NM_005263.5	c.*229T>C		3_prime_UTR_variant	7/7	ENST00000294702.6	NP_005254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFI1	ENST00000294702.6	c.*229T>C		3_prime_UTR_variant	7/7	2	NM_005263.5	ENSP00000294702	P1
GFI1	ENST00000370332.5	c.*229T>C		3_prime_UTR_variant	7/7	1		ENSP00000359357	P1
GFI1	ENST00000427103.6	c.*229T>C		3_prime_UTR_variant	7/7	1		ENSP00000399719	P1
GFI1	ENST00000696667.1	c.*129T>C		3_prime_UTR_variant	2/2			ENSP00000512792

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108135 AN: 151926 Hom.: 39148 Cov.: 31

Gnomad AFR AF: 0.804

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.677

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.629

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.646

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.700 AC: 295448 AN: 422328 Hom.: 105560 Cov.: 3 AF XY: 0.707 AC XY: 157673 AN XY: 223036

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.750

Gnomad4 ASJ exome AF: 0.666

Gnomad4 EAS exome AF: 0.959

Gnomad4 SAS exome AF: 0.842

Gnomad4 FIN exome AF: 0.640

Gnomad4 NFE exome AF: 0.644

Gnomad4 OTH exome AF: 0.688

GnomAD4 genome AF: 0.712 AC: 108229 AN: 152044 Hom.: 39187 Cov.: 31 AF XY: 0.714 AC XY: 53042 AN XY: 74294

Gnomad4 AFR AF: 0.804

Gnomad4 AMR AF: 0.704

Gnomad4 ASJ AF: 0.677

Gnomad4 EAS AF: 0.945

Gnomad4 SAS AF: 0.849

Gnomad4 FIN AF: 0.629

Gnomad4 NFE AF: 0.646

Gnomad4 OTH AF: 0.672

Alfa AF: 0.672 Hom.: 7087

Bravo AF: 0.720

Asia WGS AF: 0.880 AC: 3060 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.036
DANN	Benign	0.38

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: rs4970714; hg19: chr1-92941357;