4-125408758-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001291303.3(FAT4):​c.5884A>G​(p.Thr1962Ala) 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 benign outcome for this variant. 16/22 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)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 1 publications found

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]

FAT4 Gene-Disease associations (from GenCC):

• Hennekam lymphangiectasia-lymphedema syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• van Maldergem syndrome 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• multiple congenital anomalies/dysmorphic syndrome-intellectual disability

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Hennekam syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• van Maldergem syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06526536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.5884A>G	p.Thr1962Ala	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>G	p.Thr1962Ala	missense_variant	Exon 5 of 18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000335110.5	c.778A>G	p.Thr260Ala	missense_variant	Exon 4 of 15	1		ENSP00000335169.5
FAT4	ENST00000674496.2	c.655A>G	p.Thr219Ala	missense_variant	Exon 4 of 17			ENSP00000501473.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.074	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.64	N;N
REVEL	Benign	0.061
Sift	Benign	0.68	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0040	B;B
Vest4		0.064
MutPred		0.41		Loss of loop (P = 0.1242);.;
MVP		0.10
MPC		0.15
ClinPred		0.097	T
GERP RS		4.0
Varity_R		0.059
gMVP		0.18
Mutation Taster		=64/36	polymorphism

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: rs749792331; hg19: chr4-126329913;