4-186588632-G-C

Variant names:

• chr4-186588632-G-C
• NM_005245.4:c.13727C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005245.4(FAT1):​c.13727C>G​(p.Thr4576Arg) 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 1,461,204 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: 3.20

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19415715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT1	NM_005245.4	c.13727C>G	p.Thr4576Arg	missense_variant	Exon 27 of 27	ENST00000441802.7	NP_005236.2
FAT1	XM_005262834.4	c.13763C>G	p.Thr4588Arg	missense_variant	Exon 28 of 28		XP_005262891.1
FAT1	XM_005262835.3	c.13763C>G	p.Thr4588Arg	missense_variant	Exon 28 of 28		XP_005262892.1
FAT1	XM_006714139.4	c.13727C>G	p.Thr4576Arg	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.13727C>G	p.Thr4576Arg	missense_variant	Exon 27 of 27	5	NM_005245.4	ENSP00000406229.2
FAT1	ENST00000512772.5	c.1064C>G	p.Thr355Arg	missense_variant	Exon 4 of 4	2		ENSP00000424157.1
FAT1	ENST00000500085.2	n.1419C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
FAT1	ENST00000507105.1	c.*175C>G		downstream_gene_variant		3		ENSP00000423801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726824

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: 9.00e-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	0.080
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.70
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.000063
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.93	N;.
REVEL	Benign	0.11
Sift	Benign	0.14	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.47	P;.
Vest4		0.26
MutPred		0.16		Loss of glycosylation at T4576 (P = 0.0214);.;
MVP		0.62
MPC		0.21
ClinPred		0.32	T
GERP RS		5.3
Varity_R		0.054
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr4-187509786;