NM_005245.4:c.10660T>G

Variant names:

• chr4-186603866-A-C
• rs2637777
• NM_005245.4:c.10660T>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• 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
• Publications: 51 publications found

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]

FAT1 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis

  Inheritance: AR Classification: STRONG Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	NM_005245.4	MANE Select	c.10660T>G	p.Ser3554Ala	missense	Exon 19 of 27	NP_005236.2	Q14517
	FAT1	NM_001440456.1		c.10660T>G	p.Ser3554Ala	missense	Exon 19 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.10660T>G	p.Ser3554Ala	missense	Exon 19 of 28	NP_001427386.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	ENST00000441802.7	TSL:5 MANE Select	c.10660T>G	p.Ser3554Ala	missense	Exon 19 of 27	ENSP00000406229.2	Q14517
	FAT1	ENST00000917425.1		c.10660T>G	p.Ser3554Ala	missense	Exon 19 of 27	ENSP00000587484.1
	FAT1	ENST00000917424.1		c.10654T>G	p.Ser3552Ala	missense	Exon 19 of 27	ENSP00000587483.1

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

GnomAD2 exomes AF: 0.431 AC: 107450 AN: 249068 AF XY: 0.412

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 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

African (AFR) AF: 0.745 AC: 24957 AN: 33478

American (AMR) AF: 0.582 AC: 26015 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11958 AN: 26132

East Asian (EAS) AF: 0.649 AC: 25780 AN: 39698

South Asian (SAS) AF: 0.259 AC: 22377 AN: 86250

European-Finnish (FIN) AF: 0.382 AC: 20384 AN: 53398

Middle Eastern (MID) AF: 0.408 AC: 2351 AN: 5766

European-Non Finnish (NFE) AF: 0.358 AC: 398306 AN: 1111444

Other (OTH) AF: 0.401 AC: 24201 AN: 60360

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

African (AFR) AF: 0.733 AC: 30365 AN: 41404

American (AMR) AF: 0.532 AC: 8119 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.456 AC: 1581 AN: 3468

East Asian (EAS) AF: 0.614 AC: 3164 AN: 5152

South Asian (SAS) AF: 0.263 AC: 1265 AN: 4818

European-Finnish (FIN) AF: 0.389 AC: 4113 AN: 10582

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24890 AN: 67956

Other (OTH) AF: 0.469 AC: 988 AN: 2108

Alfa AF: 0.413 Hom.: 59189

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N
PhyloP100		0.20
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.039
Sift	Benign	0.43	T
Sift4G	Benign	0.34	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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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