rs145639192

Variant names:

• chr4-125398883-A-G
• rs145639192
• NM_001291303.3:c.5275A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001291303.3(FAT4):​c.5275A>G​(p.Ile1759Val) variant causes a missense change. The variant allele was found at a frequency of 0.00183 in 1,613,316 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (7 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 7.06
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019960731).
• BP6: Variant 4-125398883-A-G is Benign according to our data. Variant chr4-125398883-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376888.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00138 (210/152232) while in subpopulation AMR AF = 0.00347 (53/15268). AF 95% confidence interval is 0.00273. There are 0 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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.5275A>G	p.Ile1759Val	missense	Exon 3 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.5275A>G	p.Ile1759Val	missense	Exon 2 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.5275A>G	p.Ile1759Val	missense	Exon 3 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.5275A>G	p.Ile1759Val	missense	Exon 3 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.169A>G	p.Ile57Val	missense	Exon 2 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.46A>G	p.Ile16Val	missense	Exon 2 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.00138 AC: 210 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

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: 0.00191

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.000806 AC: 202 AN: 250662 AF XY: 0.000849

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00139

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00188 AC: 2745 AN: 1461084 Hom.: 7 Cov.: 30 AF XY: 0.00179 AC XY: 1300 AN XY: 726836

African (AFR) AF: 0.000209 AC: 7 AN: 33434

American (AMR) AF: 0.000984 AC: 44 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86224

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53416

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5756

European-Non Finnish (NFE) AF: 0.00229 AC: 2540 AN: 1111410

Other (OTH) AF: 0.00166 AC: 100 AN: 60348

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74416

African (AFR) AF: 0.000457 AC: 19 AN: 41544

American (AMR) AF: 0.00347 AC: 53 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68020

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00172 Hom.: 1

Bravo AF: 0.00180

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.000939 AC: 114

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00214

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	1	not provided (6)
-	1	1	not specified (2)
-	-	1	FAT4-related disorder (1)
-	1	-	Hennekam lymphangiectasia-lymphedema syndrome 2 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-1.1	N
PhyloP100		7.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.23
Sift	Benign	0.48	T
Sift4G	Uncertain	0.051	T
Polyphen		0.97	D
Vest4		0.34
MVP		0.33
MPC		0.59
ClinPred		0.053	T
GERP RS		5.8
Varity_R		0.044
gMVP		0.27
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs145639192; hg19: chr4-126320038; COSMIC: COSV100630762;