11-92353349-C-T

Variant names:

• chr11-92353349-C-T
• NM_001367949.2:c.1237C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367949.2(FAT3):​c.1237C>T​(p.Pro413Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 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: 0.0000034 (0 hom.)
• Consequence: FAT3 NM_001367949.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3305371).

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.1237C>T	p.Pro413Ser	missense	Exon 2 of 28	NP_001354878.1	Q8TDW7-1
	FAT3	NM_001008781.3		c.1237C>T	p.Pro413Ser	missense	Exon 2 of 26	NP_001008781.2	Q8TDW7-3
	FAT3	NM_001378141.1		c.1237C>T	p.Pro413Ser	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.1237C>T	p.Pro413Ser	missense	Exon 2 of 28	ENSP00000432586.2	Q8TDW7-1
	FAT3	ENST00000409404.6	TSL:5	c.1237C>T	p.Pro413Ser	missense	Exon 1 of 25	ENSP00000387040.2	Q8TDW7-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461258 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726870

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.0026
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Benign	0.15	T
Vest4		0.57
MutPred		0.32		Loss of catalytic residue at P413 (P = 0.0562)
MVP		0.45
ClinPred		0.21	T
GERP RS		5.6
Varity_R		0.13
gMVP		0.29
Mutation Taster		=62/38	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

hg19: chr11-92086515; COSMIC: COSV108139239; COSMIC: COSV108139239;