chr4-186588650-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005245.4(FAT1):​c.13709G>A​(p.Gly4570Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FAT1
NM_005245.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.52
Variant links:
Genes affected
FAT1 (HGNC:3595): (FAT atypical cadherin 1) This gene is an ortholog 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 five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell communication. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.35968316).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FAT1NM_005245.4 linkc.13709G>A p.Gly4570Asp missense_variant Exon 27 of 27 ENST00000441802.7 NP_005236.2 Q14517
FAT1XM_005262834.4 linkc.13745G>A p.Gly4582Asp missense_variant Exon 28 of 28 XP_005262891.1
FAT1XM_005262835.3 linkc.13745G>A p.Gly4582Asp missense_variant Exon 28 of 28 XP_005262892.1
FAT1XM_006714139.4 linkc.13709G>A p.Gly4570Asp missense_variant Exon 27 of 27 XP_006714202.1 Q14517

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FAT1ENST00000441802.7 linkc.13709G>A p.Gly4570Asp missense_variant Exon 27 of 27 5 NM_005245.4 ENSP00000406229.2 Q14517
FAT1ENST00000512772.5 linkc.1046G>A p.Gly349Asp missense_variant Exon 4 of 4 2 ENSP00000424157.1 H0Y9H4
FAT1ENST00000500085.2 linkn.1401G>A non_coding_transcript_exon_variant Exon 3 of 3 2
FAT1ENST00000507105.1 linkc.*157G>A downstream_gene_variant 3 ENSP00000423801.1 H0Y9C8

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000805
AC:
2
AN:
248562
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134824
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461560
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727046
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 16, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.13709G>A (p.G4570D) alteration is located in exon 27 (coding exon 26) of the FAT1 gene. This alteration results from a G to A substitution at nucleotide position 13709, causing the glycine (G) at amino acid position 4570 to be replaced by an aspartic acid (D). 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
0.10
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
21
DANN
Benign
0.97
DEOGEN2
Benign
0.12
T;T
Eigen
Benign
0.078
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.2
L;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.1
N;.
REVEL
Benign
0.14
Sift
Benign
0.074
T;.
Sift4G
Benign
0.60
T;T
Polyphen
0.96
D;.
Vest4
0.53
MutPred
0.10
Gain of glycosylation at S4566 (P = 0.0856);.;
MVP
0.65
MPC
0.25
ClinPred
0.20
T
GERP RS
4.2
Varity_R
0.15
gMVP
0.16

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.

Other links and lift over

dbSNP: rs770939534; hg19: chr4-187509804; API