rs1014867

Variant names:

• chr4-125491736-C-T
• rs1014867
• NM_001291303.3:c.14920C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291303.3(FAT4):​c.14920C>T​(p.Pro4974Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0542 in 1,613,234 control chromosomes in the GnomAD database, including 2,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (205 hom., cov: 33)
  • Exomes 𝑓: 0.055 (2278 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.697
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019827187).
• BP6: Variant 4-125491736-C-T is Benign according to our data. Variant chr4-125491736-C-T is described in ClinVar as Benign. ClinVar VariationId is 380911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

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.14920C>T	p.Pro4974Ser	missense	Exon 18 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.14920C>T	p.Pro4974Ser	missense	Exon 17 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.14917C>T	p.Pro4973Ser	missense	Exon 18 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.14920C>T	p.Pro4974Ser	missense	Exon 18 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.9637C>T	p.Pro3213Ser	missense	Exon 15 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.9691C>T	p.Pro3231Ser	missense	Exon 17 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7501 AN: 152128 Hom.: 203 Cov.: 33

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0345

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0629

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.0336

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0569

Gnomad OTH AF: 0.0455

GnomAD2 exomes AF: 0.0486 AC: 12139 AN: 249872 AF XY: 0.0486

Gnomad AFR exome AF: 0.0523

Gnomad AMR exome AF: 0.0344

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.0557

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0579

Gnomad OTH exome AF: 0.0533

GnomAD4 exome AF: 0.0547 AC: 79848 AN: 1460988 Hom.: 2278 Cov.: 33 AF XY: 0.0540 AC XY: 39230 AN XY: 726766

African (AFR) AF: 0.0526 AC: 1756 AN: 33410

American (AMR) AF: 0.0345 AC: 1539 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 456 AN: 26074

East Asian (EAS) AF: 0.0585 AC: 2320 AN: 39664

South Asian (SAS) AF: 0.0386 AC: 3327 AN: 86178

European-Finnish (FIN) AF: 0.0413 AC: 2204 AN: 53404

Middle Eastern (MID) AF: 0.0474 AC: 273 AN: 5764

European-Non Finnish (NFE) AF: 0.0583 AC: 64856 AN: 1111552

Other (OTH) AF: 0.0517 AC: 3117 AN: 60346

GnomAD4 genome AF: 0.0493 AC: 7511 AN: 152246 Hom.: 205 Cov.: 33 AF XY: 0.0469 AC XY: 3493 AN XY: 74450

African (AFR) AF: 0.0508 AC: 2112 AN: 41542

American (AMR) AF: 0.0343 AC: 524 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.0628 AC: 326 AN: 5190

South Asian (SAS) AF: 0.0350 AC: 169 AN: 4824

European-Finnish (FIN) AF: 0.0336 AC: 356 AN: 10604

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0569 AC: 3871 AN: 68012

Other (OTH) AF: 0.0459 AC: 97 AN: 2112

Alfa AF: 0.0538 Hom.: 941

Bravo AF: 0.0495

TwinsUK AF: 0.0537 AC: 199

ALSPAC AF: 0.0511 AC: 197

ESP6500AA AF: 0.0497 AC: 219

ESP6500EA AF: 0.0527 AC: 453

ExAC AF: 0.0503 AC: 6107

Asia WGS AF: 0.0560 AC: 194 AN: 3478

EpiCase AF: 0.0517

EpiControl AF: 0.0518

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.2
DANN	Benign	0.67
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.11	N
PhyloP100		0.70
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.053
Sift	Benign	0.35	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.046
MPC		0.15
ClinPred		0.0016	T
GERP RS		2.8
Varity_R		0.021
gMVP		0.11
Mutation Taster		=96/4	polymorphism (auto)

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: rs1014867; hg19: chr4-126412891; COSMIC: COSV58676858;