NM_025129.5:c.1238C>T

Variant names:

• chr19-49807170-G-A
• rs115945199
• NM_025129.5:c.1238C>T

Variant summary

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

The NM_025129.5(FUZ):​c.1238C>T​(p.Ala413Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: FUZ NM_025129.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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]

AP2A1 (HGNC:561): (adaptor related protein complex 2 subunit alpha 1) This gene encodes the alpha 1 adaptin subunit of the adaptor protein 2 (AP-2) complex found in clathrin coated vesicles. The AP-2 complex is a heterotetramer consisting of two large adaptins (alpha or beta), a medium adaptin (mu), and a small adaptin (sigma). The complex is part of the protein coat on the cytoplasmic face of coated vesicles which links clathrin to receptors in vesicles. Alternative splicing of this gene results in two transcript variants encoding two different isoforms. A third transcript variant has been described, but its full length nature has not been determined. [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=0.23493013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUZ	NM_025129.5	c.1238C>T	p.Ala413Val	missense_variant	Exon 11 of 11	ENST00000313777.9	NP_079405.2
AP2A1	NM_130787.3	c.*412G>A		downstream_gene_variant		ENST00000354293.10	NP_570603.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUZ	ENST00000313777.9	c.1238C>T	p.Ala413Val	missense_variant	Exon 11 of 11	1	NM_025129.5	ENSP00000313309.4
AP2A1	ENST00000354293.10	c.*412G>A		downstream_gene_variant		1	NM_130787.3	ENSP00000346246.4
AP2A1	ENST00000359032.10	c.*412G>A		downstream_gene_variant		5		ENSP00000351926.4

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151656 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151656 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73998

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;.;T
Eigen	Benign	0.022
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;.;M
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.086
Sift	Uncertain	0.025	D;T;T
Sift4G	Benign	0.20	T;D;T
Polyphen		0.70	P;.;P
Vest4		0.49
MutPred		0.14		.;.;Loss of disorder (P = 0.052);
MVP		0.23
MPC		0.13
ClinPred		0.55	D
GERP RS		4.3
Varity_R		0.082
gMVP		0.41

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: rs115945199; hg19: chr19-50310427;