rs17009819

Variant names:

• chr4-125487374-C-T
• rs17009819
• NM_001291303.3:c.12852C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001291303.3(FAT4):​c.12852C>T​(p.Ser4284Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,612,994 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (131 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (124 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.548
• Publications: 0 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-125487374-C-T is Benign according to our data. Variant chr4-125487374-C-T is described in ClinVar as Benign. ClinVar VariationId is 385986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.548 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0777 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	NM_001291303.3	MANE Select	c.12852C>T	p.Ser4284Ser	synonymous	Exon 17 of 18	NP_001278232.1
	FAT4	NM_001438396.1		c.12852C>T	p.Ser4284Ser	synonymous	Exon 16 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.12852C>T	p.Ser4284Ser	synonymous	Exon 17 of 18	NP_001278214.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	ENST00000394329.9	TSL:5 MANE Select	c.12852C>T	p.Ser4284Ser	synonymous	Exon 17 of 18	ENSP00000377862.4
	FAT4	ENST00000335110.5	TSL:1	c.7569C>T	p.Ser2523Ser	synonymous	Exon 14 of 15	ENSP00000335169.5
	FAT4	ENST00000674496.2		c.7623C>T	p.Ser2541Ser	synonymous	Exon 16 of 17	ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3432 AN: 151982 Hom.: 130 Cov.: 32

Gnomad AFR AF: 0.0799

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00597

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: 0.000176

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.00582 AC: 1456 AN: 250348 AF XY: 0.00452

Gnomad AFR exome AF: 0.0811

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00229 AC: 3339 AN: 1460894 Hom.: 124 Cov.: 31 AF XY: 0.00195 AC XY: 1419 AN XY: 726698

African (AFR) AF: 0.0824 AC: 2757 AN: 33446

American (AMR) AF: 0.00405 AC: 181 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39660

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86132

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53384

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5764

European-Non Finnish (NFE) AF: 0.0000855 AC: 95 AN: 1111342

Other (OTH) AF: 0.00464 AC: 280 AN: 60358

GnomAD4 genome AF: 0.0226 AC: 3443 AN: 152100 Hom.: 131 Cov.: 32 AF XY: 0.0222 AC XY: 1649 AN XY: 74360

African (AFR) AF: 0.0799 AC: 3314 AN: 41460

American (AMR) AF: 0.00596 AC: 91 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68006

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.0113 Hom.: 45

Bravo AF: 0.0259

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.4
DANN	Benign	0.58
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs17009819; hg19: chr4-126408529; COSMIC: COSV58672864;