NM_001291303.3:c.14604A>G

Variant names:

• chr4-125491420-A-G
• rs1014866
• NM_001291303.3:c.14604A>G

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.14604A>G​(p.Arg4868Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 1,613,936 control chromosomes in the GnomAD database, including 469,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42823 hom., cov: 32)
  • Exomes 𝑓: 0.76 (426633 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.917
• Publications: 27 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=-0.57).
• BP6: Variant 4-125491420-A-G is Benign according to our data. Variant chr4-125491420-A-G is described in ClinVar as Benign. ClinVar VariationId is 380802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.917 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 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.14604A>G	p.Arg4868Arg	synonymous	Exon 18 of 18	NP_001278232.1
	FAT4	NM_001438396.1		c.14604A>G	p.Arg4868Arg	synonymous	Exon 17 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.14601A>G	p.Arg4867Arg	synonymous	Exon 18 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.14604A>G	p.Arg4868Arg	synonymous	Exon 18 of 18	ENSP00000377862.4
	FAT4	ENST00000335110.5	TSL:1	c.9321A>G	p.Arg3107Arg	synonymous	Exon 15 of 15	ENSP00000335169.5
	FAT4	ENST00000674496.2		c.9375A>G	p.Arg3125Arg	synonymous	Exon 17 of 17	ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113755 AN: 151978 Hom.: 42778 Cov.: 32

Gnomad AFR AF: 0.698

Gnomad AMI AF: 0.912

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.855

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.753

GnomAD2 exomes AF: 0.758 AC: 190405 AN: 251236 AF XY: 0.759

Gnomad AFR exome AF: 0.692

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.764

Gnomad EAS exome AF: 0.874

Gnomad FIN exome AF: 0.797

Gnomad NFE exome AF: 0.759

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.763 AC: 1115791 AN: 1461840 Hom.: 426633 Cov.: 64 AF XY: 0.763 AC XY: 554791 AN XY: 727216

African (AFR) AF: 0.693 AC: 23203 AN: 33478

American (AMR) AF: 0.719 AC: 32143 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 20193 AN: 26136

East Asian (EAS) AF: 0.864 AC: 34319 AN: 39700

South Asian (SAS) AF: 0.734 AC: 63341 AN: 86258

European-Finnish (FIN) AF: 0.795 AC: 42430 AN: 53402

Middle Eastern (MID) AF: 0.720 AC: 4154 AN: 5768

European-Non Finnish (NFE) AF: 0.764 AC: 849946 AN: 1111980

Other (OTH) AF: 0.763 AC: 46062 AN: 60394

GnomAD4 genome AF: 0.749 AC: 113858 AN: 152096 Hom.: 42823 Cov.: 32 AF XY: 0.750 AC XY: 55753 AN XY: 74340

African (AFR) AF: 0.698 AC: 28953 AN: 41474

American (AMR) AF: 0.738 AC: 11283 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2677 AN: 3470

East Asian (EAS) AF: 0.855 AC: 4401 AN: 5150

South Asian (SAS) AF: 0.746 AC: 3597 AN: 4820

European-Finnish (FIN) AF: 0.793 AC: 8402 AN: 10596

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.763 AC: 51890 AN: 67968

Other (OTH) AF: 0.755 AC: 1597 AN: 2114

Alfa AF: 0.754 Hom.: 88607

Bravo AF: 0.742

Asia WGS AF: 0.796 AC: 2766 AN: 3478

EpiCase AF: 0.762

EpiControl AF: 0.760

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Hennekam lymphangiectasia-lymphedema syndrome 2 (1)
-	-	1	Van Maldergem syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.3
DANN	Benign	0.69
PhyloP100		0.92
Mutation Taster		=100/0	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: rs1014866; hg19: chr4-126412575; COSMIC: COSV108120895;