rs138019311

Variant names:

• chr4-125468676-C-T
• rs138019311
• NM_001291303.3:c.12070C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-125468676-C-T
• chr4-125468676-C-A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001291303.3(FAT4):​c.12070C>T​(p.Arg4024Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00439 in 1,614,072 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4024Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (24 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.824
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012007743).
• BP6: Variant 4-125468676-C-T is Benign according to our data. Variant chr4-125468676-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 380887.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00321 (489/152206) while in subpopulation NFE AF = 0.00519 (353/68010). AF 95% confidence interval is 0.00474. There are 0 homozygotes in GnomAd4. There are 216 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

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.12070C>T	p.Arg4024Trp	missense	Exon 12 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.12070C>T	p.Arg4024Trp	missense	Exon 11 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.12070C>T	p.Arg4024Trp	missense	Exon 12 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.12070C>T	p.Arg4024Trp	missense	Exon 12 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.6853C>T	p.Arg2285Trp	missense	Exon 10 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.6841C>T	p.Arg2281Trp	missense	Exon 11 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00411 AC: 1033 AN: 251434 AF XY: 0.00439

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00593

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00451 AC: 6598 AN: 1461866 Hom.: 24 Cov.: 32 AF XY: 0.00455 AC XY: 3308 AN XY: 727234

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00237 AC: 106 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 361 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00180 AC: 155 AN: 86258

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53418

Middle Eastern (MID) AF: 0.00832 AC: 48 AN: 5768

European-Non Finnish (NFE) AF: 0.00499 AC: 5545 AN: 1112000

Other (OTH) AF: 0.00447 AC: 270 AN: 60392

GnomAD4 genome AF: 0.00321 AC: 489 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00290 AC XY: 216 AN XY: 74410

African (AFR) AF: 0.000818 AC: 34 AN: 41540

American (AMR) AF: 0.00216 AC: 33 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3466

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

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00519 AC: 353 AN: 68010

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00522 Hom.: 7

Bravo AF: 0.00357

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00425 AC: 516

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	not specified (2)
-	-	1	FAT4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.053
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.82
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.42
MVP		0.53
MPC		0.17
ClinPred		0.043	T
GERP RS		2.4
Varity_R		0.44
gMVP		0.54
Mutation Taster		=97/3	polymorphism

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: rs138019311; hg19: chr4-126389831; COSMIC: COSV58675081;