rs2304865

Variant names:

• chr4-186604209-C-G
• rs2304865
• NM_005245.4:c.10548+168G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005245.4(FAT1):​c.10548+168G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 152,010 control chromosomes in the GnomAD database, including 6,683 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.28 (6683 hom., cov: 32)
• Consequence: FAT1 NM_005245.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.17
• Publications: 4 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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-186604209-C-G is Benign according to our data. Variant chr4-186604209-C-G is described in ClinVar as Benign. ClinVar VariationId is 1225803.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.386 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	NM_005245.4	MANE Select	c.10548+168G>C		intron	N/A	NP_005236.2
	FAT1	NM_001440456.1		c.10548+168G>C		intron	N/A	NP_001427385.1
	FAT1	NM_001440457.1		c.10548+168G>C		intron	N/A	NP_001427386.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT1	ENST00000441802.7	TSL:5 MANE Select	c.10548+168G>C		intron	N/A	ENSP00000406229.2

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43235 AN: 151890 Hom.: 6682 Cov.: 32

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.312

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.284 AC: 43235 AN: 152010 Hom.: 6683 Cov.: 32 AF XY: 0.286 AC XY: 21239 AN XY: 74282

African (AFR) AF: 0.176 AC: 7304 AN: 41480

American (AMR) AF: 0.375 AC: 5724 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1327 AN: 3472

East Asian (EAS) AF: 0.400 AC: 2065 AN: 5162

South Asian (SAS) AF: 0.234 AC: 1127 AN: 4808

European-Finnish (FIN) AF: 0.285 AC: 3008 AN: 10554

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21673 AN: 67952

Other (OTH) AF: 0.312 AC: 657 AN: 2108

Alfa AF: 0.299 Hom.: 887

Bravo AF: 0.288

Asia WGS AF: 0.288 AC: 1002 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.015
DANN	Benign	0.49
PhyloP100		-4.2
Mutation Taster		=100/0	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: rs2304865; hg19: chr4-187525363;