NM_025129.5:c.1238C>A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 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

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1718 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUZ	NM_025129.5	c.1238C>A	p.Ala413Asp	missense_variant	Exon 11 of 11	ENST00000313777.9	NP_079405.2
AP2A1	NM_130787.3	c.*412G>T		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>A	p.Ala413Asp	missense_variant	Exon 11 of 11	1	NM_025129.5	ENSP00000313309.4
AP2A1	ENST00000354293.10	c.*412G>T		downstream_gene_variant		1	NM_130787.3	ENSP00000346246.4
AP2A1	ENST00000359032.10	c.*412G>T		downstream_gene_variant		5		ENSP00000351926.4

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

GnomAD3 exomes AF: 0.00327 AC: 818 AN: 250300 Hom.: 24 AF XY: 0.00224 AC XY: 303 AN XY: 135550

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 SAS exome AF: 0.0000980

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

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.00257

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

Gnomad4 AFR AF: 0.0391

Gnomad4 AMR AF: 0.00382

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00225 Hom.: 7

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 v4.3

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;T;T
MetaRNN	Benign	0.0077	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.5	.;.;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.059
Sift	Benign	0.041	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.94	P;.;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

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;