19-55592830-C-T

Variant names:

• chr19-55592830-C-T
• rs746833483
• NM_032836.3:c.1111G>A

Variant summary

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

The NM_032836.3(FIZ1):​c.1111G>A​(p.Ala371Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.1e-7 (0 hom.)
• Consequence: FIZ1 NM_032836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.273

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=0.14741683).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIZ1	NM_032836.3	c.1111G>A	p.Ala371Thr	missense_variant	Exon 3 of 3	ENST00000221665.5	NP_116225.2
FIZ1	XM_005259352.5	c.1111G>A	p.Ala371Thr	missense_variant	Exon 3 of 3		XP_005259409.1
FIZ1	XM_047439564.1	c.1111G>A	p.Ala371Thr	missense_variant	Exon 2 of 2		XP_047295520.1
FIZ1	XM_011527426.3	c.1093G>A	p.Ala365Thr	missense_variant	Exon 2 of 2		XP_011525728.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIZ1	ENST00000221665.5	c.1111G>A	p.Ala371Thr	missense_variant	Exon 3 of 3	1	NM_032836.3	ENSP00000221665.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417474 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 703274

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: 0.0000170

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000509 Hom.: 0

ExAC AF: 0.00000965 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1111G>A (p.A371T) 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 1111, causing the alanine (A) at amino acid position 371 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	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.065
Sift	Benign	0.16	T
Sift4G	Benign	0.41	T
Polyphen		0.89	P
Vest4		0.083
MutPred		0.36		Gain of glycosylation at A371 (P = 0.0296);
MVP		0.32
ClinPred		0.43	T
GERP RS		3.4
Varity_R		0.079
gMVP		0.17

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: rs746833483; hg19: chr19-56104196;