rs72928772

Variant names:

• chr4-125316816-C-T
• rs72928772
• NM_001291303.3:c.405C>T
• FAT4 p.Phe135Phe

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.405C>T​(p.Phe135Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,613,560 control chromosomes in the GnomAD database, including 36,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2631 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33935 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.37
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 4-125316816-C-T is Benign according to our data. Variant chr4-125316816-C-T is described in ClinVar as Benign. ClinVar VariationId is 380815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.223 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.405C>T	p.Phe135Phe	synonymous	Exon 2 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.405C>T	p.Phe135Phe	synonymous	Exon 1 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.405C>T	p.Phe135Phe	synonymous	Exon 2 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.405C>T	p.Phe135Phe	synonymous	Exon 2 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000674496.2		c.-55+839C>T		intron	N/A	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26505 AN: 152028 Hom.: 2630 Cov.: 32

Gnomad AFR AF: 0.0876

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.185 AC: 46000 AN: 248304 AF XY: 0.189

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.201

GnomAD4 exome AF: 0.212 AC: 310007 AN: 1461414 Hom.: 33935 Cov.: 35 AF XY: 0.211 AC XY: 153756 AN XY: 726984

African (AFR) AF: 0.0806 AC: 2698 AN: 33476

American (AMR) AF: 0.126 AC: 5632 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 5555 AN: 26134

East Asian (EAS) AF: 0.107 AC: 4246 AN: 39682

South Asian (SAS) AF: 0.169 AC: 14553 AN: 86238

European-Finnish (FIN) AF: 0.225 AC: 12000 AN: 53300

Middle Eastern (MID) AF: 0.151 AC: 870 AN: 5768

European-Non Finnish (NFE) AF: 0.227 AC: 252689 AN: 1111770

Other (OTH) AF: 0.195 AC: 11764 AN: 60368

GnomAD4 genome AF: 0.174 AC: 26508 AN: 152146 Hom.: 2631 Cov.: 32 AF XY: 0.174 AC XY: 12907 AN XY: 74364

African (AFR) AF: 0.0876 AC: 3639 AN: 41532

American (AMR) AF: 0.150 AC: 2298 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 706 AN: 3472

East Asian (EAS) AF: 0.112 AC: 579 AN: 5166

South Asian (SAS) AF: 0.161 AC: 775 AN: 4822

European-Finnish (FIN) AF: 0.238 AC: 2521 AN: 10574

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15336 AN: 67972

Other (OTH) AF: 0.176 AC: 371 AN: 2108

Alfa AF: 0.203 Hom.: 6365

Bravo AF: 0.162

Asia WGS AF: 0.140 AC: 489 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		2.4
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs72928772;

hg19: chr4-126237971;

COSMIC: COSV67886260;