rs749792331

chr4-125408758-A-Cchr4-125408758-A-Gchr4-125408758-A-T

Variant summary

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

The NM_001291303.3(FAT4):c.5884A>C(p.Thr1962Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1962S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96

Genes affected

FAT4 (HGNC:23109): (FAT atypical cadherin 4) The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Mar 2014]

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=0.20974973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAT4	NM_001291303.3	c.5884A>C	p.Thr1962Pro	missense_variant	5/18	ENST00000394329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAT4	ENST00000394329.9	c.5884A>C	p.Thr1962Pro	missense_variant	5/18	5	NM_001291303.3	P1
FAT4	ENST00000335110.5	c.778A>C	p.Thr260Pro	missense_variant	4/15	1
FAT4	ENST00000674496.2	c.655A>C	p.Thr219Pro	missense_variant	4/17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000427 AC: 1 AN: 234104 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440914 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 716392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-0.026
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.47	N;.
MutationTaster	Benign	0.59	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.15
Sift	Benign	0.34	T;T
Sift4G	Uncertain	0.032	D;D
Polyphen		0.87	P;P
Vest4		0.42
MutPred		0.40		Loss of glycosylation at T1962 (P = 0.1441);.;
MVP		0.32
MPC		0.40
ClinPred		0.26	T
GERP RS		4.0
Varity_R		0.15
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs749792331; hg19: chr4-126329913; COSMIC: COSV58687825;