19-49807348-C-T

Variant names:

• chr19-49807348-C-T
• rs139365610
• NM_025129.5:c.1060G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_025129.5(FUZ):​c.1060G>A​(p.Asp354Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,613,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D354Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00069 (0 hom.)
• Consequence: FUZ NM_025129.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.02
• Publications: 8 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]

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046576858).
• BP6: Variant 19-49807348-C-T is Benign according to our data. Variant chr19-49807348-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 707831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1060G>A	p.Asp354Asn	missense	Exon 11 of 11	NP_079405.2
	FUZ	NM_001352262.2		c.1063G>A	p.Asp355Asn	missense	Exon 11 of 11	NP_001339191.1
	FUZ	NM_001171937.2		c.952G>A	p.Asp318Asn	missense	Exon 10 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.1060G>A	p.Asp354Asn	missense	Exon 11 of 11	ENSP00000313309.4	Q9BT04-1
	FUZ	ENST00000881282.1		c.1141G>A	p.Asp381Asn	missense	Exon 12 of 12	ENSP00000551341.1
	FUZ	ENST00000881283.1		c.1081G>A	p.Asp361Asn	missense	Exon 11 of 11	ENSP00000551342.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152050 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000814 AC: 203 AN: 249378 AF XY: 0.00101

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.000712

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000685 AC: 1001 AN: 1461248 Hom.: 0 Cov.: 37 AF XY: 0.000753 AC XY: 547 AN XY: 726900

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.000134 AC: 6 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00251 AC: 216 AN: 86212

European-Finnish (FIN) AF: 0.000754 AC: 40 AN: 53028

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000630 AC: 701 AN: 1111876

Other (OTH) AF: 0.000530 AC: 32 AN: 60386

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152168 Hom.: 0 Cov.: 31 AF XY: 0.000444 AC XY: 33 AN XY: 74384

African (AFR) AF: 0.0000722 AC: 3 AN: 41542

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68008

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000898 AC: 109

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.0
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Uncertain	0.028	D
Sift4G	Benign	0.16	T
Polyphen		0.49	P
Vest4		0.16
MVP		0.12
MPC		0.57
ClinPred		0.020	T
GERP RS		3.3
Varity_R		0.068
gMVP		0.29
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs139365610; hg19: chr19-50310605; COSMIC: COSV58241635; COSMIC: COSV58241635;