4-125318831-C-T

Variant names:

• chr4-125318831-C-T
• rs1039808
• NM_001291303.3:c.2420C>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.2420C>T​(p.Ala807Val) variant causes a missense change. The variant allele was found at a frequency of 0.438 in 1,613,752 control chromosomes in the GnomAD database, including 157,577 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A807A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.46 (16453 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141124 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.68
• Publications: 43 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=2.4184585E-4).
• BP6: Variant 4-125318831-C-T is Benign according to our data. Variant chr4-125318831-C-T is described in ClinVar as Benign. ClinVar VariationId is 380329.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 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.2420C>T	p.Ala807Val	missense	Exon 2 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.2420C>T	p.Ala807Val	missense	Exon 1 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.2420C>T	p.Ala807Val	missense	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.2420C>T	p.Ala807Val	missense	Exon 2 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000674496.2		c.-55+2854C>T		intron	N/A	ENSP00000501473.2	A0A7P0T1I0
	FAT4	ENST00000678072.1		n.26C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69743 AN: 151826 Hom.: 16427 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.413 AC: 103088 AN: 249352 AF XY: 0.412

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.443

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.436 AC: 636920 AN: 1461808 Hom.: 141124 Cov.: 69 AF XY: 0.434 AC XY: 315491 AN XY: 727216

African (AFR) AF: 0.576 AC: 19291 AN: 33480

American (AMR) AF: 0.381 AC: 17027 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9507 AN: 26134

East Asian (EAS) AF: 0.236 AC: 9379 AN: 39700

South Asian (SAS) AF: 0.406 AC: 35028 AN: 86254

European-Finnish (FIN) AF: 0.390 AC: 20842 AN: 53394

Middle Eastern (MID) AF: 0.354 AC: 2043 AN: 5768

European-Non Finnish (NFE) AF: 0.448 AC: 498518 AN: 1111968

Other (OTH) AF: 0.419 AC: 25285 AN: 60392

GnomAD4 genome AF: 0.460 AC: 69823 AN: 151944 Hom.: 16453 Cov.: 32 AF XY: 0.454 AC XY: 33725 AN XY: 74268

African (AFR) AF: 0.567 AC: 23475 AN: 41412

American (AMR) AF: 0.403 AC: 6149 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1223 AN: 3472

East Asian (EAS) AF: 0.244 AC: 1256 AN: 5152

South Asian (SAS) AF: 0.387 AC: 1862 AN: 4814

European-Finnish (FIN) AF: 0.393 AC: 4147 AN: 10558

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.445 AC: 30268 AN: 67950

Other (OTH) AF: 0.434 AC: 918 AN: 2116

Alfa AF: 0.442 Hom.: 72226

Bravo AF: 0.463

TwinsUK AF: 0.463 AC: 1715

ALSPAC AF: 0.441 AC: 1700

ESP6500AA AF: 0.542 AC: 2195

ESP6500EA AF: 0.426 AC: 3568

ExAC AF: 0.422 AC: 51004

Asia WGS AF: 0.341 AC: 1189 AN: 3478

EpiCase AF: 0.432

EpiControl AF: 0.427

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		3.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Uncertain	0.016	D
Polyphen		0.57	P
Vest4		0.13
MPC		0.50
ClinPred		0.020	T
GERP RS		5.1
Varity_R		0.26
gMVP		0.26
Mutation Taster		=97/3	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: rs1039808; hg19: chr4-126239986; COSMIC: COSV67882879;