chr4-125408758-A-T

Variant names:

• chr4-125408758-A-T
• rs749792331
• NM_001291303.3:c.5884A>T

Variant summary

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

The NM_001291303.3(FAT4):​c.5884A>T​(p.Thr1962Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 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=0.05340779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.5884A>T	p.Thr1962Ser	missense_variant	Exon 5 of 18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.5884A>T	p.Thr1962Ser	missense_variant	Exon 5 of 18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000335110.5	c.778A>T	p.Thr260Ser	missense_variant	Exon 4 of 15	1		ENSP00000335169.5
FAT4	ENST00000674496.2	c.655A>T	p.Thr219Ser	missense_variant	Exon 4 of 17			ENSP00000501473.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000854 AC: 2 AN: 234104 Hom.: 0 AF XY: 0.00000789 AC XY: 1 AN XY: 126748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000627

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000139 AC: 2 AN: 1440914 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 716392

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000474

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 23, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.83
DEOGEN2	Benign	0.039	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.043
Sift	Benign	0.72	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.019	B;B
Vest4		0.13
MutPred		0.43		Gain of disorder (P = 0.0782);.;
MVP		0.093
MPC		0.14
ClinPred		0.042	T
GERP RS		4.0
Varity_R		0.054
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;