rs7680937

Variant names:

• chr4-186588338-C-T
• rs7680937
• NM_005245.4:c.*254G>A

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.*254G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 460,638 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (205 hom., cov: 32)
  • Exomes 𝑓: 0.014 (118 hom.)
• Consequence: FAT1 NM_005245.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0600
• Publications: 1 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 (BayesDel_noAF=-0.86).
• BP6: Variant 4-186588338-C-T is Benign according to our data. Variant chr4-186588338-C-T is described in ClinVar as Benign. ClinVar VariationId is 1274388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0924 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.*254G>A		3_prime_UTR	Exon 27 of 27	NP_005236.2	Q14517
	FAT1	NM_001440456.1		c.*254G>A		3_prime_UTR	Exon 28 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.*254G>A		3_prime_UTR	Exon 28 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.*254G>A		3_prime_UTR	Exon 27 of 27	ENSP00000406229.2	Q14517
	FAT1	ENST00000917425.1		c.*254G>A		3_prime_UTR	Exon 27 of 27	ENSP00000587484.1
	FAT1	ENST00000917424.1		c.*254G>A		3_prime_UTR	Exon 27 of 27	ENSP00000587483.1

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4938 AN: 152020 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.0250

GnomAD4 exome AF: 0.0135 AC: 4169 AN: 308498 Hom.: 118 Cov.: 3 AF XY: 0.0125 AC XY: 1962 AN XY: 157244

African (AFR) AF: 0.0954 AC: 996 AN: 10444

American (AMR) AF: 0.0140 AC: 151 AN: 10768

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 163 AN: 10712

East Asian (EAS) AF: 0.0639 AC: 1616 AN: 25298

South Asian (SAS) AF: 0.00469 AC: 74 AN: 15790

European-Finnish (FIN) AF: 0.00303 AC: 64 AN: 21152

Middle Eastern (MID) AF: 0.0108 AC: 16 AN: 1482

European-Non Finnish (NFE) AF: 0.00412 AC: 796 AN: 193308

Other (OTH) AF: 0.0150 AC: 293 AN: 19544

GnomAD4 genome AF: 0.0325 AC: 4944 AN: 152140 Hom.: 205 Cov.: 32 AF XY: 0.0315 AC XY: 2343 AN XY: 74402

African (AFR) AF: 0.0948 AC: 3936 AN: 41506

American (AMR) AF: 0.0190 AC: 290 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3466

East Asian (EAS) AF: 0.0429 AC: 222 AN: 5172

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4830

European-Finnish (FIN) AF: 0.00378 AC: 40 AN: 10574

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00462 AC: 314 AN: 67986

Other (OTH) AF: 0.0247 AC: 52 AN: 2104

Alfa AF: 0.0178 Hom.: 276

Bravo AF: 0.0367

Asia WGS AF: 0.0290 AC: 103 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.24
DANN	Benign	0.64
PhyloP100		0.060
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: rs7680937; hg19: chr4-187509492;