chr5-151521835-C-A

Variant names:

• chr5-151521835-C-A
• rs770597316
• NM_001447.3:c.10758G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001447.3(FAT2):​c.10758G>T​(p.Lys3586Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FAT2 NM_001447.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.682
• Publications: 0 publications found

Genes affected

FAT2 (HGNC:3596): (FAT atypical cadherin 2) This gene is the second identified human homolog 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 two epidermal growth factor (EGF)-like repeats and one laminin G domain. This protein most likely functions as a cell adhesion molecule, controlling cell proliferation and playing an important role in cerebellum development. [provided by RefSeq, Jul 2008]

SLC36A1 (HGNC:18761): (solute carrier family 36 member 1) This gene encodes a member of the eukaryote-specific amino acid/auxin permease (AAAP) 1 transporter family. The encoded protein functions as a proton-dependent, small amino acid transporter. This gene is clustered with related family members on chromosome 5q33.1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001447.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT2	NM_001447.3	MANE Select	c.10758G>T	p.Lys3586Asn	missense	Exon 19 of 24	NP_001438.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT2	ENST00000261800.6	TSL:1 MANE Select	c.10758G>T	p.Lys3586Asn	missense	Exon 19 of 24	ENSP00000261800.5
	FAT2	ENST00000520200.5	TSL:1	c.1332G>T	p.Lys444Asn	missense	Exon 6 of 11	ENSP00000429678.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.68
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.45		Loss of ubiquitination at K3586 (P = 0.0192)
MVP		0.75
MPC		0.59
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.60
gMVP		0.71
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs770597316; hg19: chr5-150901396;