4-186588632-G-A

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.13727C>T(p.Thr4576Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,613,450 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.20

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=0.004844308).
• BP6: Variant 4-186588632-G-A is Benign according to our data. Variant chr4-186588632-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 783387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00991 (1509/152248) while in subpopulation AFR AF= 0.0347 (1441/41530). AF 95% confidence interval is 0.0332. There are 28 homozygotes in gnomad4. There are 698 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT1	NM_005245.4	c.13727C>T	p.Thr4576Met	missense_variant	27/27	ENST00000441802.7
FAT1	XM_005262834.4	c.13763C>T	p.Thr4588Met	missense_variant	28/28
FAT1	XM_005262835.3	c.13763C>T	p.Thr4588Met	missense_variant	28/28
FAT1	XM_006714139.4	c.13727C>T	p.Thr4576Met	missense_variant	27/27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT1	ENST00000441802.7	c.13727C>T	p.Thr4576Met	missense_variant	27/27	5	NM_005245.4	P1
FAT1	ENST00000512772.5	c.1067C>T	p.Thr356Met	missense_variant	4/4	2
FAT1	ENST00000500085.2	n.1419C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00989 AC: 1504 AN: 152130 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

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: 0.000235

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00255 AC: 634 AN: 248344 Hom.: 5 AF XY: 0.00201 AC XY: 271 AN XY: 134662

Gnomad AFR exome AF: 0.0352

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.00111 AC: 1622 AN: 1461202 Hom.: 19 Cov.: 31 AF XY: 0.000958 AC XY: 696 AN XY: 726824

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00991 AC: 1509 AN: 152248 Hom.: 28 Cov.: 32 AF XY: 0.00938 AC XY: 698 AN XY: 74450

Gnomad4 AFR AF: 0.0347

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00174 Hom.: 6

Bravo AF: 0.0113

ESP6500AA AF: 0.0303 AC: 127

ESP6500EA AF: 0.000357 AC: 3

ExAC AF: 0.00299 AC: 362

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The FAT1 p.Thr4576Met variant was not identified in the literature nor was it identified in LOVD 3.0 or Cosmic. The variant was identified in dbSNP (ID: rs142057401) and ClinVar (classified as benign by Invitae). The variant was identified in control databases in 948 of 279736 chromosomes (11 homozygous) at a frequency of 0.003389 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 854 of 24180 chromosomes (freq: 0.03532), Latino in 58 of 35310 chromosomes (freq: 0.001643), Other in 6 of 7116 chromosomes (freq: 0.000843), European (non-Finnish) in 24 of 127842 chromosomes (freq: 0.000188), East Asian in 3 of 19516 chromosomes (freq: 0.000154) and South Asian in 3 of 30556 chromosomes (freq: 0.000098), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Thr4576 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.087	T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.13	N;.
REVEL	Benign	0.13
Sift	Benign	0.042	D;.
Sift4G	Benign	0.11	T;T
Polyphen		0.93	P;.
Vest4		0.33
MVP		0.69
MPC		0.24
ClinPred		0.031	T
GERP RS		5.3
Varity_R		0.031
gMVP		0.19

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: rs142057401; hg19: chr4-187509786; COSMIC: COSV99072776; COSMIC: COSV99072776;