11-92352921-C-T

Position:

• chr11-92352921-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367949.2(FAT3):​c.809C>T​(p.Thr270Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: FAT3 NM_001367949.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35937178).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT3	NM_001367949.2	c.809C>T	p.Thr270Ile	missense_variant	2/28	ENST00000525166.6	NP_001354878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT3	ENST00000525166.6	c.809C>T	p.Thr270Ile	missense_variant	2/28	5	NM_001367949.2	ENSP00000432586.2
FAT3	ENST00000409404.6	c.809C>T	p.Thr270Ile	missense_variant	1/25	5		ENSP00000387040.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461646 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2021

The c.809C>T (p.T270I) alteration is located in exon 1 (coding exon 1) of the FAT3 gene. This alteration results from a C to T substitution at nucleotide position 809, causing the threonine (T) at amino acid position 270 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.11
Sift	Benign	0.056	T;T
Vest4		0.51
MutPred		0.45		Loss of glycosylation at T270 (P = 0.0279);.;
MVP		0.31
ClinPred		0.86	D
GERP RS		4.2
Varity_R		0.074
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-92086087;