rs368721486

Variant names:

• chr19-49808759-C-A
• rs368721486
• NM_025129.5:c.851G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49808759-C-A
• chr19-49808759-C-G
• chr19-49808759-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_025129.5(FUZ):​c.851G>T​(p.Arg284Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000387 in 1,577,126 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: FUZ NM_025129.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 1.67
• Publications: 4 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)

ENSG00000269194 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-49808759-C-A is Pathogenic according to our data. Variant chr19-49808759-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446687.Status of the report is no_assertion_criteria_provided, 0 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.851G>T	p.Arg284Leu	missense	Exon 8 of 11	NP_079405.2
	FUZ	NM_001352262.2		c.851G>T	p.Arg284Leu	missense	Exon 8 of 11	NP_001339191.1
	FUZ	NM_001171937.2		c.743G>T	p.Arg248Leu	missense	Exon 7 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.851G>T	p.Arg284Leu	missense	Exon 8 of 11	ENSP00000313309.4	Q9BT04-1
	FUZ	ENST00000881282.1		c.932G>T	p.Arg311Leu	missense	Exon 9 of 12	ENSP00000551341.1
	FUZ	ENST00000881283.1		c.851G>T	p.Arg284Leu	missense	Exon 8 of 11	ENSP00000551342.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD2 exomes AF: 0.0000107 AC: 2 AN: 186816 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000256

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000400 AC: 57 AN: 1424784 Hom.: 0 Cov.: 33 AF XY: 0.0000368 AC XY: 26 AN XY: 705628

African (AFR) AF: 0.00 AC: 0 AN: 32714

American (AMR) AF: 0.0000256 AC: 1 AN: 39066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 37584

South Asian (SAS) AF: 0.00 AC: 0 AN: 81962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50144

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5726

European-Non Finnish (NFE) AF: 0.0000439 AC: 48 AN: 1093222

Other (OTH) AF: 0.000102 AC: 6 AN: 58888

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74500

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000168 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	1	-	Jeune thoracic dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.075	T
Polyphen		1.0	D
Vest4		0.64
MVP		0.28
MPC		0.18
ClinPred		0.93	D
GERP RS		4.3
PromoterAI		-0.061	Neutral
Varity_R		0.41
gMVP		0.78
Mutation Taster		=32/68	disease causing (ClinVar)

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: rs368721486; hg19: chr19-50312016; COSMIC: COSV58240938; COSMIC: COSV58240938;