chr4-186603866-A-C

Position:

• chr4-186603866-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005245.4(FAT1):​c.10660T>G​(p.Ser3554Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,613,202 control chromosomes in the GnomAD database, including 132,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20534 hom., cov: 32)
  • Exomes 𝑓: 0.38 (112220 hom.)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.198

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=1.4539924E-6).
• BP6: Variant 4-186603866-A-C is Benign according to our data. Variant chr4-186603866-A-C is described in ClinVar as [Benign]. Clinvar id is 1268969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT1	NM_005245.4	c.10660T>G	p.Ser3554Ala	missense_variant	19/27	ENST00000441802.7	NP_005236.2
FAT1	XM_005262834.4	c.10660T>G	p.Ser3554Ala	missense_variant	19/28		XP_005262891.1
FAT1	XM_005262835.3	c.10660T>G	p.Ser3554Ala	missense_variant	19/28		XP_005262892.1
FAT1	XM_006714139.4	c.10660T>G	p.Ser3554Ala	missense_variant	19/27		XP_006714202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7	c.10660T>G	p.Ser3554Ala	missense_variant	19/27	5	NM_005245.4	ENSP00000406229	P1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74805 AN: 151844 Hom.: 20495 Cov.: 32

Gnomad AFR AF: 0.733

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.614

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.472

GnomAD3 exomes AF: 0.431 AC: 107450 AN: 249068 Hom.: 25708 AF XY: 0.412 AC XY: 55613 AN XY: 135116

Gnomad AFR exome AF: 0.741

Gnomad AMR exome AF: 0.592

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.625

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.385

Gnomad NFE exome AF: 0.364

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.381 AC: 556329 AN: 1461240 Hom.: 112220 Cov.: 37 AF XY: 0.375 AC XY: 272645 AN XY: 726910

Gnomad4 AFR exome AF: 0.745

Gnomad4 AMR exome AF: 0.582

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.649

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.382

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.401

GnomAD4 genome AF: 0.493 AC: 74898 AN: 151962 Hom.: 20534 Cov.: 32 AF XY: 0.493 AC XY: 36597 AN XY: 74278

Gnomad4 AFR AF: 0.733

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.614

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.469

Alfa AF: 0.393 Hom.: 25053

Bravo AF: 0.522

TwinsUK AF: 0.341 AC: 1266

ALSPAC AF: 0.350 AC: 1350

ESP6500AA AF: 0.708 AC: 2723

ESP6500EA AF: 0.362 AC: 2990

ExAC AF: 0.427 AC: 51629

EpiCase AF: 0.364

EpiControl AF: 0.365

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.69
DANN	Benign	0.45
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.24	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.74	N;.
REVEL	Benign	0.039
Sift	Benign	0.43	T;.
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;.
Vest4		0.041
MPC		0.079
ClinPred		0.0035	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.15

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: rs2637777; hg19: chr4-187525020; COSMIC: COSV71673371; COSMIC: COSV71673371;