rs1105168

chr5-151507321-G-Achr5-151507321-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0860

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]

SLC36A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FAT2
• 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/exons	MANE	UniProt
FAT2	NM_001447.3	c.12350C>T	p.Pro4117Leu	missense_variant	23/24	ENST00000261800.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT2	ENST00000261800.6	c.12350C>T	p.Pro4117Leu	missense_variant	23/24	1	NM_001447.3	P1
FAT2	ENST00000520200.5	c.2669C>T	p.Pro890Leu	missense_variant	10/11	1

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102065 AN: 151958 Hom.: 35698 Cov.: 31

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

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.: 82 AF XY: 0.595 AC XY: 432763 AN XY: 727246

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.: 31 AF XY: 0.675 AC XY: 50188 AN XY: 74350

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

FAT2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	1.4
Dann	Benign	0.29
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.22	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.097
Sift	Benign	0.65	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.12
ClinPred		0.0014	T
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

Other links and lift over

dbSNP: rs1105168; hg19: chr5-150886882; COSMIC: COSV55813273; COSMIC: COSV55813273;