rs6836935

Variant names:

• chr4-186621773-T-C
• rs6836935
• NM_005245.4:c.4813A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-186621773-T-C
• chr4-186621773-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005245.4(FAT1):​c.4813A>G​(p.Asn1605Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,550,142 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (50 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (39 hom.)
• Consequence: FAT1 NM_005245.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.02
• Publications: 6 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=0.006181717).
• BP6: Variant 4-186621773-T-C is Benign according to our data. Variant chr4-186621773-T-C is described in ClinVar as Benign. ClinVar VariationId is 778168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2032/152266) while in subpopulation AFR AF = 0.0469 (1946/41520). AF 95% confidence interval is 0.0451. There are 50 homozygotes in GnomAd4. There are 942 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR gene

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.4813A>G	p.Asn1605Asp	missense splice_region	Exon 10 of 27	NP_005236.2	Q14517
	FAT1	NM_001440456.1		c.4813A>G	p.Asn1605Asp	missense splice_region	Exon 10 of 28	NP_001427385.1
	FAT1	NM_001440457.1		c.4813A>G	p.Asn1605Asp	missense splice_region	Exon 10 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.4813A>G	p.Asn1605Asp	missense splice_region	Exon 10 of 27	ENSP00000406229.2	Q14517
	FAT1	ENST00000917425.1		c.4813A>G	p.Asn1605Asp	missense splice_region	Exon 10 of 27	ENSP00000587484.1
	FAT1	ENST00000917424.1		c.4813A>G	p.Asn1605Asp	missense splice_region	Exon 10 of 27	ENSP00000587483.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2017 AN: 152148 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00379 AC: 678 AN: 178806 AF XY: 0.00286

Gnomad AFR exome AF: 0.0497

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.000726

Gnomad EAS exome AF: 0.0000683

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00148 AC: 2067 AN: 1397876 Hom.: 39 Cov.: 32 AF XY: 0.00127 AC XY: 875 AN XY: 689924

African (AFR) AF: 0.0513 AC: 1612 AN: 31432

American (AMR) AF: 0.00220 AC: 74 AN: 33604

Ashkenazi Jewish (ASJ) AF: 0.000760 AC: 18 AN: 23678

East Asian (EAS) AF: 0.00 AC: 0 AN: 38950

South Asian (SAS) AF: 0.0000517 AC: 4 AN: 77404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48026

Middle Eastern (MID) AF: 0.00670 AC: 37 AN: 5522

European-Non Finnish (NFE) AF: 0.000144 AC: 156 AN: 1081476

Other (OTH) AF: 0.00287 AC: 166 AN: 57784

GnomAD4 genome AF: 0.0133 AC: 2032 AN: 152266 Hom.: 50 Cov.: 33 AF XY: 0.0127 AC XY: 942 AN XY: 74464

African (AFR) AF: 0.0469 AC: 1946 AN: 41520

American (AMR) AF: 0.00334 AC: 51 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68028

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00443 Hom.: 54

Bravo AF: 0.0148

ESP6500AA AF: 0.0368 AC: 131

ESP6500EA AF: 0.000253 AC: 2

ExAC AF: 0.00367 AC: 439

Asia WGS AF: 0.00346 AC: 12 AN: 3478

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	0.34
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.44
MPC		0.53
ClinPred		0.024	T
GERP RS		5.1
Varity_R		0.69
gMVP		0.41
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs6836935; hg19: chr4-187542927; COSMIC: COSV99081606;