19-49808445-A-T

Variant names:

• chr19-49808445-A-T
• rs375291937
• NM_025129.5:c.1002T>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025129.5(FUZ):​c.1002T>A​(p.Tyr334*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y334Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FUZ NM_025129.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 0 publications found

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]

FUZ Gene-Disease associations (from GenCC):

• neural tube defects, susceptibility to

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025129.5. 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
	FUZ	NM_025129.5	MANE Select	c.1002T>A	p.Tyr334*	stop_gained	Exon 10 of 11	NP_079405.2
	FUZ	NM_001352262.2		c.1005T>A	p.Tyr335*	stop_gained	Exon 10 of 11	NP_001339191.1
	FUZ	NM_001171937.2		c.894T>A	p.Tyr298*	stop_gained	Exon 9 of 10	NP_001165408.1	Q9BT04-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUZ	ENST00000313777.9	TSL:1 MANE Select	c.1002T>A	p.Tyr334*	stop_gained	Exon 10 of 11	ENSP00000313309.4	Q9BT04-1
	FUZ	ENST00000881282.1		c.1083T>A	p.Tyr361*	stop_gained	Exon 11 of 12	ENSP00000551341.1
	FUZ	ENST00000881283.1		c.1002T>A	p.Tyr334*	stop_gained	Exon 10 of 11	ENSP00000551342.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460364 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726426

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111624

Other (OTH) AF: 0.00 AC: 0 AN: 60314

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.074	N
PhyloP100		-0.078
Vest4		0.83
GERP RS		-3.2
PromoterAI		0.021	Neutral
Mutation Taster		=28/172	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs375291937; hg19: chr19-50311702;