1-92483501-T-G

Variant names:

• chr1-92483501-T-G
• rs200972824
• NM_005263.5:c.-14A>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005263.5(GFI1):​c.-14A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,486,092 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: GFI1 NM_005263.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.356
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-92483501-T-G is Benign according to our data. Variant chr1-92483501-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 538142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 155 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFI1	NM_005263.5	MANE Select	c.-14A>C		5_prime_UTR	Exon 2 of 7	NP_005254.2
	GFI1	NM_001127215.3		c.-14A>C		5_prime_UTR	Exon 2 of 7	NP_001120687.1
	GFI1	NM_001127216.3		c.-14A>C		5_prime_UTR	Exon 2 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.-14A>C		5_prime_UTR	Exon 2 of 7	ENSP00000294702.5
	GFI1	ENST00000370332.5	TSL:1	c.-14A>C		5_prime_UTR	Exon 2 of 7	ENSP00000359357.1
	GFI1	ENST00000427103.6	TSL:1	c.-14A>C		5_prime_UTR	Exon 2 of 7	ENSP00000399719.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00121 AC: 270 AN: 222980 AF XY: 0.00107

Gnomad AFR exome AF: 0.000451

Gnomad AMR exome AF: 0.0000936

Gnomad ASJ exome AF: 0.000732

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00792

Gnomad NFE exome AF: 0.000969

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00121 AC: 1611 AN: 1333802 Hom.: 1 Cov.: 22 AF XY: 0.00113 AC XY: 758 AN XY: 668788

African (AFR) AF: 0.000292 AC: 9 AN: 30832

American (AMR) AF: 0.000117 AC: 5 AN: 42848

Ashkenazi Jewish (ASJ) AF: 0.000555 AC: 14 AN: 25216

East Asian (EAS) AF: 0.00 AC: 0 AN: 38206

South Asian (SAS) AF: 0.00 AC: 0 AN: 82110

European-Finnish (FIN) AF: 0.00662 AC: 345 AN: 52098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5514

European-Non Finnish (NFE) AF: 0.00119 AC: 1194 AN: 1000920

Other (OTH) AF: 0.000785 AC: 44 AN: 56058

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74482

African (AFR) AF: 0.000144 AC: 6 AN: 41564

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000396 Hom.: 0

Bravo AF: 0.000654

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Neutropenia, severe congenital, 2, autosomal dominant (2)
-	-	1	GFI1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.54
PhyloP100		-0.36
PromoterAI		0.0049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs200972824; hg19: chr1-92949058;