rs1105168

Variant names:

• chr5-151507321-G-A
• rs1105168
• NM_001447.3:c.12350C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-151507321-G-A
• chr5-151507321-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001447.3(FAT2):​c.12350C>T​(p.Pro4117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.599 in 1,613,958 control chromosomes in the GnomAD database, including 297,016 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4117T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.67 (35740 hom., cov: 31)
  • Exomes 𝑓: 0.59 (261276 hom.)
• Consequence: FAT2 NM_001447.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0860
• Publications: 37 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.74588E-7).
• BP6: Variant 5-151507321-G-A is Benign according to our data. Variant chr5-151507321-G-A is described in ClinVar as Benign. ClinVar VariationId is 1249251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT2	NM_001447.3	MANE Select	c.12350C>T	p.Pro4117Leu	missense	Exon 23 of 24	NP_001438.1	Q9NYQ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT2	ENST00000261800.6	TSL:1 MANE Select	c.12350C>T	p.Pro4117Leu	missense	Exon 23 of 24	ENSP00000261800.5	Q9NYQ8
	FAT2	ENST00000520200.5	TSL:1	c.2666C>T	p.Pro889Leu	missense	Exon 10 of 11	ENSP00000429678.1	H0YBK2

Frequencies

GnomAD3 genomes AF: 0.672 AC: 102065 AN: 151958 Hom.: 35698 Cov.: 31

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.573

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.601

GnomAD2 exomes AF: 0.659 AC: 165792 AN: 251486 AF XY: 0.656

Gnomad AFR exome AF: 0.873

Gnomad AMR exome AF: 0.738

Gnomad ASJ exome AF: 0.568

Gnomad EAS exome AF: 0.844

Gnomad FIN exome AF: 0.605

Gnomad NFE exome AF: 0.561

Gnomad OTH exome AF: 0.602

GnomAD4 exome AF: 0.591 AC: 864440 AN: 1461880 Hom.: 261276 Cov.: 82 AF XY: 0.595 AC XY: 432763 AN XY: 727246

African (AFR) AF: 0.868 AC: 29066 AN: 33480

American (AMR) AF: 0.728 AC: 32574 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 14786 AN: 26136

East Asian (EAS) AF: 0.837 AC: 33220 AN: 39700

South Asian (SAS) AF: 0.785 AC: 67704 AN: 86258

European-Finnish (FIN) AF: 0.598 AC: 31941 AN: 53418

Middle Eastern (MID) AF: 0.643 AC: 3705 AN: 5766

European-Non Finnish (NFE) AF: 0.553 AC: 614472 AN: 1112004

Other (OTH) AF: 0.612 AC: 36972 AN: 60394

GnomAD4 genome AF: 0.672 AC: 102168 AN: 152078 Hom.: 35740 Cov.: 31 AF XY: 0.675 AC XY: 50188 AN XY: 74350

African (AFR) AF: 0.862 AC: 35758 AN: 41502

American (AMR) AF: 0.650 AC: 9929 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 1986 AN: 3468

East Asian (EAS) AF: 0.839 AC: 4343 AN: 5176

South Asian (SAS) AF: 0.800 AC: 3853 AN: 4814

European-Finnish (FIN) AF: 0.605 AC: 6392 AN: 10568

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37848 AN: 67956

Other (OTH) AF: 0.599 AC: 1263 AN: 2108

Alfa AF: 0.596 Hom.: 104688

Bravo AF: 0.684

TwinsUK AF: 0.550 AC: 2040

ALSPAC AF: 0.545 AC: 2100

ESP6500AA AF: 0.858 AC: 3780

ESP6500EA AF: 0.549 AC: 4721

ExAC AF: 0.664 AC: 80639

Asia WGS AF: 0.803 AC: 2792 AN: 3478

EpiCase AF: 0.553

EpiControl AF: 0.552

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FAT2-related disorder (1)
-	-	1	Spinocerebellar ataxia 45 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.4
DANN	Benign	0.29
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.22	N
PhyloP100		0.086
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.097
Sift	Benign	0.65	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.12
ClinPred		0.0014	T
GERP RS		0.26
Varity_R		0.019
gMVP		0.11
Mutation Taster		=90/10	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: rs1105168; hg19: chr5-150886882; COSMIC: COSV55813273; COSMIC: COSV55813273;