chr11-92352664-C-A

Variant names:

• chr11-92352664-C-A
• rs536537428
• NM_001367949.2:c.552C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001367949.2(FAT3):​c.552C>A​(p.Asp184Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D184D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAT3 NM_001367949.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.111
• Publications: 0 publications found

Genes affected

FAT3 (HGNC:23112): (FAT atypical cadherin 3) Predicted to enable calcium ion binding activity. Predicted to be involved in cell-cell adhesion. Predicted to act upstream of or within several processes, including negative regulation of dendrite development; neuron migration; and retina layer formation. Predicted to be located in dendrite and plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367949.2. 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
	FAT3	NM_001367949.2	MANE Select	c.552C>A	p.Asp184Glu	missense	Exon 2 of 28	NP_001354878.1	Q8TDW7-1
	FAT3	NM_001008781.3		c.552C>A	p.Asp184Glu	missense	Exon 2 of 26	NP_001008781.2	Q8TDW7-3
	FAT3	NM_001378141.1		c.552C>A	p.Asp184Glu	missense	Exon 2 of 4	NP_001365070.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT3	ENST00000525166.6	TSL:5 MANE Select	c.552C>A	p.Asp184Glu	missense	Exon 2 of 28	ENSP00000432586.2	Q8TDW7-1
	FAT3	ENST00000409404.6	TSL:5	c.552C>A	p.Asp184Glu	missense	Exon 1 of 25	ENSP00000387040.2	Q8TDW7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461516 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	0.33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		0.11
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Vest4		0.94
MutPred		0.93		Gain of loop (P = 0.1069)
MVP		0.93
ClinPred		0.99	D
GERP RS		1.6
Varity_R		0.44
gMVP		0.76
Mutation Taster		=54/46	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: rs536537428; hg19: chr11-92085830;