19-49808486-G-C

Position:

• chr19-49808486-G-C

Variant summary

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

The NM_025129.5(FUZ):​c.961C>G​(p.Pro321Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,459,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FUZ NM_025129.5 missense, splice_region
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.95

Genes affected

FUZ (HGNC:26219): (fuzzy planar cell polarity protein) This gene encodes a planar cell polarity protein that is involved in ciliogenesis and directional cell movement. Knockout studies in mice exhibit neural tube defects and defective cilia, and mutations in this gene are associated with neural tube defects in humans. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2012]

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=0.1735369).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FUZ	NM_025129.5	c.961C>G	p.Pro321Ala	missense_variant, splice_region_variant	10/11	ENST00000313777.9	NP_079405.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FUZ	ENST00000313777.9	c.961C>G	p.Pro321Ala	missense_variant, splice_region_variant	10/11	1	NM_025129.5	ENSP00000313309	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459024 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725600

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

research

Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo

Feb 08, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	.;.;T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.099
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;M
MutationTaster	Benign	0.55	D;D;D;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.082	T;T;T
Polyphen		0.94	P;.;P
Vest4		0.37
MutPred		0.20		.;.;Loss of glycosylation at P321 (P = 0.0163);
MVP		0.27
MPC		0.57
ClinPred		0.76	D
GERP RS		3.7
Varity_R		0.049
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50311743;