rs1280100

Variant names:

• chr4-186616979-A-G
• rs1280100
• NM_005245.4:c.9075+26T>C

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.9075+26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.59 in 1,585,358 control chromosomes in the GnomAD database, including 279,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33468 hom., cov: 33)
  • Exomes 𝑓: 0.58 (246123 hom.)
• Consequence: FAT1 NM_005245.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.179
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 4-186616979-A-G is Benign according to our data. Variant chr4-186616979-A-G is described in ClinVar as [Benign]. Clinvar id is 1271179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT1	NM_005245.4	c.9075+26T>C		intron_variant	Intron 11 of 26	ENST00000441802.7	NP_005236.2
FAT1	NM_001440456.1	c.9075+26T>C		intron_variant	Intron 11 of 27		NP_001427385.1
FAT1	NM_001440457.1	c.9075+26T>C		intron_variant	Intron 11 of 27		NP_001427386.1
FAT1	NM_001440455.1	c.9075+26T>C		intron_variant	Intron 11 of 26		NP_001427384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7	c.9075+26T>C		intron_variant	Intron 11 of 26	5	NM_005245.4	ENSP00000406229.2

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99465 AN: 151966 Hom.: 33413 Cov.: 33

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.600

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.636

GnomAD2 exomes AF: 0.605 AC: 141144 AN: 233460 AF XY: 0.592

Gnomad AFR exome AF: 0.828

Gnomad AMR exome AF: 0.688

Gnomad ASJ exome AF: 0.627

Gnomad EAS exome AF: 0.679

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.576

Gnomad OTH exome AF: 0.596

GnomAD4 exome AF: 0.583 AC: 835478 AN: 1433274 Hom.: 246123 Cov.: 25 AF XY: 0.578 AC XY: 411839 AN XY: 712268

African (AFR) AF: 0.831 AC: 26815 AN: 32254

American (AMR) AF: 0.682 AC: 27806 AN: 40800

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 15475 AN: 24918

East Asian (EAS) AF: 0.690 AC: 27162 AN: 39368

South Asian (SAS) AF: 0.455 AC: 37586 AN: 82618

European-Finnish (FIN) AF: 0.588 AC: 31021 AN: 52774

Middle Eastern (MID) AF: 0.604 AC: 3410 AN: 5646

European-Non Finnish (NFE) AF: 0.576 AC: 630904 AN: 1095664

Other (OTH) AF: 0.596 AC: 35299 AN: 59232

GnomAD4 genome AF: 0.655 AC: 99585 AN: 152084 Hom.: 33468 Cov.: 33 AF XY: 0.654 AC XY: 48641 AN XY: 74358

African (AFR) AF: 0.818 AC: 33940 AN: 41502

American (AMR) AF: 0.666 AC: 10178 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2121 AN: 3470

East Asian (EAS) AF: 0.676 AC: 3491 AN: 5162

South Asian (SAS) AF: 0.453 AC: 2182 AN: 4816

European-Finnish (FIN) AF: 0.600 AC: 6337 AN: 10562

Middle Eastern (MID) AF: 0.592 AC: 173 AN: 292

European-Non Finnish (NFE) AF: 0.578 AC: 39275 AN: 67980

Other (OTH) AF: 0.634 AC: 1340 AN: 2112

Alfa AF: 0.601 Hom.: 20576

Bravo AF: 0.673

Asia WGS AF: 0.583 AC: 2033 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.40
DANN	Benign	0.34
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1280100; hg19: chr4-187538133; COSMIC: COSV71672985;