4-186588777-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005245.4(FAT1):c.13582G>A(p.Glu4528Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00546 in 1,613,982 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (38 hom.)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047872365).
• BP6: Variant 4-186588777-C-T is Benign according to our data. Variant chr4-186588777-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 791620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186588777-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00437 (665/152274) while in subpopulation NFE AF= 0.00622 (423/68020). AF 95% confidence interval is 0.00573. There are 3 homozygotes in gnomad4. There are 341 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.13582G>A	p.Glu4528Lys	missense_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4	c.13618G>A	p.Glu4540Lys	missense_variant	28/28
FAT1	XM_005262835.3	c.13618G>A	p.Glu4540Lys	missense_variant	28/28
FAT1	XM_006714139.4	c.13582G>A	p.Glu4528Lys	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.13582G>A	p.Glu4528Lys	missense_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000512772.5	c.922G>A	p.Glu308Lys	missense_variant	4/4	2
FAT1	ENST00000500085.2	n.1274G>A		non_coding_transcript_exon_variant	3/3	2
FAT1	ENST00000507105.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152156 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00538 AC: 1341 AN: 249212 Hom.: 9 AF XY: 0.00539 AC XY: 728 AN XY: 135190

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.00768

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00557 AC: 8148 AN: 1461708 Hom.: 38 Cov.: 31 AF XY: 0.00542 AC XY: 3944 AN XY: 727134

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.0169

Gnomad4 NFE exome AF: 0.00613

Gnomad4 OTH exome AF: 0.00421

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152274 Hom.: 3 Cov.: 32 AF XY: 0.00458 AC XY: 341 AN XY: 74448

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.00622

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00526 Hom.: 2

Bravo AF: 0.00348

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00120 AC: 5

ESP6500EA AF: 0.00794 AC: 67

ExAC AF: 0.00637 AC: 771

EpiCase AF: 0.00534

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	FAT1: BP4, BS2 -

FAT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.99	N;.
REVEL	Benign	0.19
Sift	Benign	0.19	T;.
Sift4G	Uncertain	0.031	D;D
Polyphen		0.78	P;.
Vest4		0.35
MVP		0.42
MPC		0.13
ClinPred		0.038	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.22

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: rs192609167; hg19: chr4-187509931; COSMIC: COSV104437725; COSMIC: COSV104437725;