rs1567047

Variant names:

• chr4-125451587-G-A
• rs1567047
• NM_001291303.3:c.10577G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-125451587-G-A
• chr4-125451587-G-C
• chr4-125451587-G-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.10577G>A​(p.Gly3526Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,874 control chromosomes in the GnomAD database, including 65,712 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G3526G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (4646 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61066 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.80
• Publications: 35 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=0.0034423769).
• BP6: Variant 4-125451587-G-A is Benign according to our data. Variant chr4-125451587-G-A is described in ClinVar as Benign. ClinVar VariationId is 380813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 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.10577G>A	p.Gly3526Asp	missense	Exon 10 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.10577G>A	p.Gly3526Asp	missense	Exon 9 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.10577G>A	p.Gly3526Asp	missense	Exon 10 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.10577G>A	p.Gly3526Asp	missense	Exon 10 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.5465G>A	p.Gly1822Asp	missense	Exon 9 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.5348G>A	p.Gly1783Asp	missense	Exon 9 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34068 AN: 151900 Hom.: 4637 Cov.: 32

Gnomad AFR AF: 0.0641

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.248

GnomAD2 exomes AF: 0.272 AC: 68286 AN: 251236 AF XY: 0.277

Gnomad AFR exome AF: 0.0591

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.420

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.285 AC: 416655 AN: 1461854 Hom.: 61066 Cov.: 81 AF XY: 0.286 AC XY: 207893 AN XY: 727230

African (AFR) AF: 0.0556 AC: 1860 AN: 33480

American (AMR) AF: 0.244 AC: 10934 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 7134 AN: 26136

East Asian (EAS) AF: 0.411 AC: 16330 AN: 39700

South Asian (SAS) AF: 0.291 AC: 25076 AN: 86258

European-Finnish (FIN) AF: 0.239 AC: 12778 AN: 53420

Middle Eastern (MID) AF: 0.220 AC: 1271 AN: 5768

European-Non Finnish (NFE) AF: 0.292 AC: 324640 AN: 1111972

Other (OTH) AF: 0.275 AC: 16632 AN: 60396

GnomAD4 genome AF: 0.224 AC: 34099 AN: 152020 Hom.: 4646 Cov.: 32 AF XY: 0.223 AC XY: 16603 AN XY: 74296

African (AFR) AF: 0.0640 AC: 2657 AN: 41522

American (AMR) AF: 0.247 AC: 3770 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 973 AN: 3468

East Asian (EAS) AF: 0.407 AC: 2092 AN: 5134

South Asian (SAS) AF: 0.279 AC: 1339 AN: 4800

European-Finnish (FIN) AF: 0.241 AC: 2543 AN: 10570

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19774 AN: 67960

Other (OTH) AF: 0.252 AC: 532 AN: 2112

Alfa AF: 0.273 Hom.: 27893

Bravo AF: 0.220

TwinsUK AF: 0.297 AC: 1101

ALSPAC AF: 0.302 AC: 1163

ESP6500AA AF: 0.0663 AC: 292

ESP6500EA AF: 0.300 AC: 2578

ExAC AF: 0.267 AC: 32446

Asia WGS AF: 0.314 AC: 1092 AN: 3478

EpiCase AF: 0.291

EpiControl AF: 0.290

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	2	Van Maldergem syndrome 2 (2)
-	-	1	Hennekam lymphangiectasia-lymphedema syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.88
MPC		0.74
ClinPred		0.026	T
GERP RS		5.8
Varity_R		0.41
gMVP		0.72
Mutation Taster		=28/72	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: rs1567047; hg19: chr4-126372742; COSMIC: COSV58676353; COSMIC: COSV58676353;