NM_005263.5:c.*229T>C

Variant names:

• chr1-92475800-A-G
• rs4970714
• NM_005263.5:c.*229T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 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: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
GFI1	NM_005263.5	c.*229T>C		3_prime_UTR_variant	Exon 7 of 7	ENST00000294702.6	NP_005254.2

Ensembl

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

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

African (AFR) AF: 0.808 AC: 9763 AN: 12084

American (AMR) AF: 0.750 AC: 13994 AN: 18666

Ashkenazi Jewish (ASJ) AF: 0.666 AC: 8611 AN: 12938

East Asian (EAS) AF: 0.959 AC: 27349 AN: 28512

South Asian (SAS) AF: 0.842 AC: 38642 AN: 45870

European-Finnish (FIN) AF: 0.640 AC: 16801 AN: 26238

Middle Eastern (MID) AF: 0.714 AC: 1308 AN: 1832

European-Non Finnish (NFE) AF: 0.644 AC: 162206 AN: 251818

Other (OTH) AF: 0.688 AC: 16774 AN: 24370

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

African (AFR) AF: 0.804 AC: 33349 AN: 41492

American (AMR) AF: 0.704 AC: 10754 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 2345 AN: 3466

East Asian (EAS) AF: 0.945 AC: 4885 AN: 5170

South Asian (SAS) AF: 0.849 AC: 4097 AN: 4824

European-Finnish (FIN) AF: 0.629 AC: 6624 AN: 10538

Middle Eastern (MID) AF: 0.677 AC: 199 AN: 294

European-Non Finnish (NFE) AF: 0.646 AC: 43886 AN: 67956

Other (OTH) AF: 0.672 AC: 1417 AN: 2110

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.036
DANN	Benign	0.38
PhyloP100		-2.9
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: rs4970714; hg19: chr1-92941357;