19-55593364-C-T

Position:

• chr19-55593364-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032836.3(FIZ1):​c.577G>A​(p.Ala193Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FIZ1 NM_032836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.432

Genes affected

FIZ1 (HGNC:25917): (FLT3 interacting zinc finger 1) This gene encodes zinc finger protein, which interacts with a receptor tyrosine kinase involved in the regulation of hematopoietic and lymphoid cells. This gene product also interacts with a transcription factor that regulates the expression of rod-specific genes in retina. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13172108).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FIZ1	NM_032836.3	c.577G>A	p.Ala193Thr	missense_variant	3/3	ENST00000221665.5	NP_116225.2
FIZ1	XM_005259352.5	c.577G>A	p.Ala193Thr	missense_variant	3/3		XP_005259409.1
FIZ1	XM_047439564.1	c.577G>A	p.Ala193Thr	missense_variant	2/2		XP_047295520.1
FIZ1	XM_011527426.3	c.559G>A	p.Ala187Thr	missense_variant	2/2		XP_011525728.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FIZ1	ENST00000221665.5	c.577G>A	p.Ala193Thr	missense_variant	3/3	1	NM_032836.3	ENSP00000221665.2
FIZ1	ENST00000590714.1	c.577G>A	p.Ala193Thr	missense_variant	2/2	1		ENSP00000465131.1
FIZ1	ENST00000592585.1	c.*135G>A		downstream_gene_variant		5		ENSP00000468529.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1204454 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 584642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.577G>A (p.A193T) alteration is located in exon 3 (coding exon 2) of the FIZ1 gene. This alteration results from a G to A substitution at nucleotide position 577, causing the alanine (A) at amino acid position 193 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0037	N
LIST_S2	Benign	0.58	T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.16	N;.
REVEL	Benign	0.025
Sift	Benign	0.51	T;.
Sift4G	Benign	0.40	T;.
Polyphen		0.012	B;.
Vest4		0.33
MutPred		0.35		Gain of glycosylation at A193 (P = 0.0087);Gain of glycosylation at A193 (P = 0.0087);
MVP		0.19
ClinPred		0.060	T
GERP RS		1.6
Varity_R		0.050
gMVP		0.24

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: rs1305274269; hg19: chr19-56104730;