NM_001447.3:c.12350C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001447.3(FAT2):c.12350C>T(p.Pro4117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 1,613,958 control chromosomes in the GnomAD database, including 297,016 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4117M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.67 ( 35740 hom., cov: 31)

Exomes 𝑓: 0.59 ( 261276 hom. )

Consequence

FAT2
NM_001447.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0860

Variant links:

Genes affected

FAT2 (HGNC:3596): (FAT atypical cadherin 2) This gene is the second identified human homolog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has two epidermal growth factor (EGF)-like repeats and one laminin G domain. This protein most likely functions as a cell adhesion molecule, controlling cell proliferation and playing an important role in cerebellum development. [provided by RefSeq, Jul 2008]

FAT2 links:

SLC36A1 (HGNC:18761): (solute carrier family 36 member 1) This gene encodes a member of the eukaryote-specific amino acid/auxin permease (AAAP) 1 transporter family. The encoded protein functions as a proton-dependent, small amino acid transporter. This gene is clustered with related family members on chromosome 5q33.1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

SLC36A1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.74588E-7).

BP6

Variant 5-151507321-G-A is Benign according to our data. Variant chr5-151507321-G-A is described in ClinVar as [Benign]. Clinvar id is 1249251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT2	NM_001447.3 link	c.12350C>T	p.Pro4117Leu	missense_variant	Exon 23 of 24	ENST00000261800.6	NP_001438.1	Q9NYQ8Q6PIA2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT2	ENST00000261800.6 link	c.12350C>T	p.Pro4117Leu	missense_variant	Exon 23 of 24	1	NM_001447.3	ENSP00000261800.5		Q9NYQ8
FAT2	ENST00000520200.5 link	c.2666C>T	p.Pro889Leu	missense_variant	Exon 10 of 11	1		ENSP00000429678.1		H0YBK2

Frequencies

GnomAD3 genomes

AF:

0.672

AC:

102065

AN:

151958

Hom.:

35698

Cov.:

show subpopulations

Gnomad AFR

AF:

0.862

Gnomad AMI

AF:

0.659

Gnomad AMR

AF:

0.649

Gnomad ASJ

AF:

0.573

Gnomad EAS

AF:

0.838

Gnomad SAS

AF:

0.801

Gnomad FIN

AF:

0.605

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.557

Gnomad OTH

AF:

0.601

GnomAD3 exomes

AF:

0.659

AC:

165792

AN:

251486

Hom.:

56427

AF XY:

0.656

AC XY:

89131

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.873

Gnomad AMR exome

AF:

0.738

Gnomad ASJ exome

AF:

0.568

Gnomad EAS exome

AF:

0.844

Gnomad SAS exome

AF:

0.793

Gnomad FIN exome

AF:

0.605

Gnomad NFE exome

AF:

0.561

Gnomad OTH exome

AF:

0.602

GnomAD4 exome

AF:

0.591

AC:

864440

AN:

1461880

Hom.:

261276

Cov.:

AF XY:

0.595

AC XY:

432763

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.868

Gnomad4 AMR exome

AF:

0.728

Gnomad4 ASJ exome

AF:

0.566

Gnomad4 EAS exome

AF:

0.837

Gnomad4 SAS exome

AF:

0.785

Gnomad4 FIN exome

AF:

0.598

Gnomad4 NFE exome

AF:

0.553

Gnomad4 OTH exome

AF:

0.612

GnomAD4 genome

AF:

0.672

AC:

102168

AN:

152078

Hom.:

35740

Cov.:

AF XY:

0.675

AC XY:

50188

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.862

Gnomad4 AMR

AF:

0.650

Gnomad4 ASJ

AF:

0.573

Gnomad4 EAS

AF:

0.839

Gnomad4 SAS

AF:

0.800

Gnomad4 FIN

AF:

0.605

Gnomad4 NFE

AF:

0.557

Gnomad4 OTH

AF:

0.599

Alfa

AF:

0.588

Hom.:

50850

Bravo

AF:

0.684

TwinsUK

AF:

0.550

AC:

2040

ALSPAC

AF:

0.545

AC:

2100

ESP6500AA

AF:

0.858

AC:

3780

ESP6500EA

AF:

0.549

AC:

4721

ExAC

AF:

0.664

AC:

80639

Asia WGS

AF:

0.803

AC:

2792

AN:

3478

EpiCase

AF:

0.553

EpiControl

AF:

0.552

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FAT2-related disorder

Benign:1

Jul 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Spinocerebellar ataxia 45

Benign:1

Aug 10, 2021

Genome-Nilou Lab

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

0.061

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

1.4

DANN

Benign

0.29

DEOGEN2

Benign

0.013

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.38

MetaRNN

Benign

6.7e-7

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.22

PrimateAI

Benign

0.22

PROVEAN

Benign

0.13

REVEL

Benign

0.097

Sift

Benign

0.65

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.028

MPC

0.12

ClinPred

0.0014

GERP RS

0.26

Varity_R

0.019

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over