4-186588652-G-T

Variant names:

• chr4-186588652-G-T
• NM_005245.4:c.13707C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005245.4(FAT1):​c.13707C>A​(p.Asp4569Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAT1 NM_005245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032818645).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT1	NM_005245.4	c.13707C>A	p.Asp4569Glu	missense_variant	Exon 27 of 27	ENST00000441802.7	NP_005236.2
FAT1	XM_005262834.4	c.13743C>A	p.Asp4581Glu	missense_variant	Exon 28 of 28		XP_005262891.1
FAT1	XM_005262835.3	c.13743C>A	p.Asp4581Glu	missense_variant	Exon 28 of 28		XP_005262892.1
FAT1	XM_006714139.4	c.13707C>A	p.Asp4569Glu	missense_variant	Exon 27 of 27		XP_006714202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT1	ENST00000441802.7	c.13707C>A	p.Asp4569Glu	missense_variant	Exon 27 of 27	5	NM_005245.4	ENSP00000406229.2
FAT1	ENST00000512772.5	c.1044C>A	p.Asp348Glu	missense_variant	Exon 4 of 4	2		ENSP00000424157.1
FAT1	ENST00000500085.2	n.1399C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
FAT1	ENST00000507105.1	c.*155C>A		downstream_gene_variant		3		ENSP00000423801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461604 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.0010
DANN	Benign	0.36
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.46	N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.14	N;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.
Sift4G	Benign	0.92	T;T
Polyphen		0.062	B;.
Vest4		0.055
MutPred		0.27		Gain of glycosylation at Y4564 (P = 7e-04);.;
MVP		0.13
MPC		0.095
ClinPred		0.056	T
GERP RS		-6.7
Varity_R		0.049
gMVP		0.087

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-187509806;