19-49807170-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025129.5(FUZ):​c.1238C>A​(p.Ala413Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,613,274 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (38 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (42 hom.)
• Consequence: FUZ NM_025129.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.07
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076666176).
• BP6: Variant 19-49807170-G-T is Benign according to our data. Variant chr19-49807170-G-T is described in ClinVar as Benign. ClinVar VariationId is 446002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1718/151764) while in subpopulation AFR AF = 0.0391 (1619/41364). AF 95% confidence interval is 0.0376. There are 38 homozygotes in GnomAd4. There are 809 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUZ	NM_025129.5	MANE Select	c.1238C>A	p.Ala413Asp	missense	Exon 11 of 11	NP_079405.2
	FUZ	NM_001352262.2		c.1241C>A	p.Ala414Asp	missense	Exon 11 of 11	NP_001339191.1
	FUZ	NM_001171937.2		c.1130C>A	p.Ala377Asp	missense	Exon 10 of 10	NP_001165408.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FUZ	ENST00000313777.9	TSL:1 MANE Select	c.1238C>A	p.Ala413Asp	missense	Exon 11 of 11	ENSP00000313309.4
	FUZ	ENST00000528094.5	TSL:2	c.1130C>A	p.Ala377Asp	missense	Exon 10 of 10	ENSP00000435177.1
	FUZ	ENST00000533418.5	TSL:5	c.1088C>A	p.Ala363Asp	missense	Exon 11 of 11	ENSP00000431731.1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1714 AN: 151646 Hom.: 38 Cov.: 31

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00382

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: 0.000235

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00327 AC: 818 AN: 250300 AF XY: 0.00224

Gnomad AFR exome AF: 0.0437

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00138 AC: 2023 AN: 1461510 Hom.: 42 Cov.: 37 AF XY: 0.00114 AC XY: 832 AN XY: 727038

African (AFR) AF: 0.0451 AC: 1510 AN: 33478

American (AMR) AF: 0.00257 AC: 115 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5766

European-Non Finnish (NFE) AF: 0.000174 AC: 194 AN: 1111880

Other (OTH) AF: 0.00257 AC: 155 AN: 60376

GnomAD4 genome AF: 0.0113 AC: 1718 AN: 151764 Hom.: 38 Cov.: 31 AF XY: 0.0109 AC XY: 809 AN XY: 74120

African (AFR) AF: 0.0391 AC: 1619 AN: 41364

American (AMR) AF: 0.00382 AC: 58 AN: 15194

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67966

Other (OTH) AF: 0.0119 AC: 25 AN: 2100

Alfa AF: 0.00466 Hom.: 20

Bravo AF: 0.0131

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0420 AC: 185

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00405 AC: 492

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.059
Sift	Benign	0.041	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.73
MVP		0.34
MPC		0.19
ClinPred		0.011	T
GERP RS		4.3
Varity_R		0.29
gMVP		0.70
Mutation Taster		=100/0	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: rs115945199; hg19: chr19-50310427;