NM_001291303.3:c.8021A>C

Variant names:

• chr4-125449031-A-C
• rs138655269
• NM_001291303.3:c.8021A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001291303.3(FAT4):​c.8021A>C​(p.Asp2674Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2674V) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.14
• Publications: 3 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):

• FAT4-related neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291303.3. 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
	FAT4	NM_001291303.3	MANE Select	c.8021A>C	p.Asp2674Ala	missense	Exon 10 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.8021A>C	p.Asp2674Ala	missense	Exon 9 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.8021A>C	p.Asp2674Ala	missense	Exon 10 of 18	NP_001278214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	ENST00000394329.9	TSL:5 MANE Select	c.8021A>C	p.Asp2674Ala	missense	Exon 10 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.2909A>C	p.Asp970Ala	missense	Exon 9 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.2792A>C	p.Asp931Ala	missense	Exon 9 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 41

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.34	N
PhyloP100		9.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.39
Sift	Benign	0.90	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.34		Gain of glycosylation at S2676 (P = 0.0453)
MVP		0.58
MPC		0.67
ClinPred		0.83	D
GERP RS		5.9
Varity_R		0.11
gMVP		0.64
Mutation Taster		=47/53	disease causing

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: rs138655269; hg19: chr4-126370186;