rs34631763

Variant names:

• chr1-92483381-C-T
• rs34631763
• NM_005263.5:c.107G>A

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.107G>A​(p.Ser36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,602,830 control chromosomes in the GnomAD database, including 2,489 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S36L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.040 (183 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2306 hom.)
• Consequence: GFI1 NM_005263.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 2.50
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018077791).
• BP6: Variant 1-92483381-C-T is Benign according to our data. Variant chr1-92483381-C-T is described in ClinVar as Benign. ClinVar VariationId is 259699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0577 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.107G>A	p.Ser36Asn	missense	Exon 2 of 7	NP_005254.2	Q99684
	GFI1	NM_001127215.3		c.107G>A	p.Ser36Asn	missense	Exon 2 of 7	NP_001120687.1	Q99684
	GFI1	NM_001127216.3		c.107G>A	p.Ser36Asn	missense	Exon 2 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.107G>A	p.Ser36Asn	missense	Exon 2 of 7	ENSP00000294702.5	Q99684
	GFI1	ENST00000370332.5	TSL:1	c.107G>A	p.Ser36Asn	missense	Exon 2 of 7	ENSP00000359357.1	Q99684
	GFI1	ENST00000427103.6	TSL:1	c.107G>A	p.Ser36Asn	missense	Exon 2 of 7	ENSP00000399719.1	Q99684

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6151 AN: 152242 Hom.: 183 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0430

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0592

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0397 AC: 9753 AN: 245864 AF XY: 0.0394

Gnomad AFR exome AF: 0.00945

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0568

Gnomad NFE exome AF: 0.0564

Gnomad OTH exome AF: 0.0456

GnomAD4 exome AF: 0.0521 AC: 75620 AN: 1450470 Hom.: 2306 Cov.: 29 AF XY: 0.0512 AC XY: 36943 AN XY: 722128

African (AFR) AF: 0.00743 AC: 247 AN: 33246

American (AMR) AF: 0.0292 AC: 1305 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.0697 AC: 1814 AN: 26030

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39598

South Asian (SAS) AF: 0.00977 AC: 839 AN: 85886

European-Finnish (FIN) AF: 0.0559 AC: 2966 AN: 53056

Middle Eastern (MID) AF: 0.0221 AC: 124 AN: 5616

European-Non Finnish (NFE) AF: 0.0593 AC: 65322 AN: 1102460

Other (OTH) AF: 0.0500 AC: 2999 AN: 59960

GnomAD4 genome AF: 0.0404 AC: 6151 AN: 152360 Hom.: 183 Cov.: 33 AF XY: 0.0407 AC XY: 3030 AN XY: 74508

African (AFR) AF: 0.0102 AC: 426 AN: 41590

American (AMR) AF: 0.0429 AC: 657 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0651 AC: 226 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4832

European-Finnish (FIN) AF: 0.0585 AC: 621 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0592 AC: 4030 AN: 68030

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0518 Hom.: 475

Bravo AF: 0.0369

TwinsUK AF: 0.0663 AC: 246

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0545 AC: 469

ExAC AF: 0.0377 AC: 4572

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0552

EpiControl AF: 0.0552

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	1	Neutropenia, severe congenital, 2, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.0087
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.057
Sift	Benign	0.063	T
Sift4G	Benign	0.50	T
Polyphen		0.026	B
Vest4		0.046
MPC		0.60
ClinPred		0.015	T
GERP RS		4.3
Varity_R		0.15
gMVP		0.062
Mutation Taster		=98/2	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: rs34631763; hg19: chr1-92948938; COSMIC: COSV54042707;