4-125317769-A-T

Variant names:

• chr4-125317769-A-T
• rs6847454
• NM_001291303.3:c.1358A>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.1358A>T​(p.Gln453Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,613,882 control chromosomes in the GnomAD database, including 157,747 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q453R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.46 (16452 hom., cov: 32)
  • Exomes 𝑓: 0.44 (141295 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.151
• Publications: 33 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=2.3591885E-5).
• BP6: Variant 4-125317769-A-T is Benign according to our data. Variant chr4-125317769-A-T is described in ClinVar as Benign. ClinVar VariationId is 380812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.56 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.1358A>T	p.Gln453Leu	missense	Exon 2 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.1358A>T	p.Gln453Leu	missense	Exon 1 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.1358A>T	p.Gln453Leu	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.1358A>T	p.Gln453Leu	missense	Exon 2 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000674496.2		c.-55+1792A>T		intron	N/A	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69802 AN: 151946 Hom.: 16426 Cov.: 32

Gnomad AFR AF: 0.566

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.254

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.439

GnomAD2 exomes AF: 0.414 AC: 103306 AN: 249260 AF XY: 0.413

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.444

Gnomad OTH exome AF: 0.411

GnomAD4 exome AF: 0.436 AC: 637658 AN: 1461818 Hom.: 141295 Cov.: 71 AF XY: 0.434 AC XY: 315813 AN XY: 727204

African (AFR) AF: 0.576 AC: 19287 AN: 33480

American (AMR) AF: 0.381 AC: 17037 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9508 AN: 26136

East Asian (EAS) AF: 0.255 AC: 10110 AN: 39700

South Asian (SAS) AF: 0.406 AC: 35007 AN: 86254

European-Finnish (FIN) AF: 0.390 AC: 20788 AN: 53370

Middle Eastern (MID) AF: 0.354 AC: 2042 AN: 5768

European-Non Finnish (NFE) AF: 0.448 AC: 498544 AN: 1111994

Other (OTH) AF: 0.419 AC: 25335 AN: 60394

GnomAD4 genome AF: 0.460 AC: 69882 AN: 152064 Hom.: 16452 Cov.: 32 AF XY: 0.454 AC XY: 33731 AN XY: 74318

African (AFR) AF: 0.567 AC: 23519 AN: 41512

American (AMR) AF: 0.402 AC: 6154 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1223 AN: 3468

East Asian (EAS) AF: 0.254 AC: 1306 AN: 5138

South Asian (SAS) AF: 0.386 AC: 1853 AN: 4806

European-Finnish (FIN) AF: 0.390 AC: 4131 AN: 10584

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30254 AN: 67950

Other (OTH) AF: 0.434 AC: 919 AN: 2116

Alfa AF: 0.400 Hom.: 3650

Bravo AF: 0.464

TwinsUK AF: 0.462 AC: 1714

ALSPAC AF: 0.441 AC: 1699

ESP6500AA AF: 0.545 AC: 2215

ESP6500EA AF: 0.427 AC: 3559

ExAC AF: 0.423 AC: 51126

Asia WGS AF: 0.343 AC: 1198 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	0.081
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	9.6
DANN	Benign	0.82
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.000024	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.28	N
PhyloP100		0.15
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.018
Sift	Benign	0.33	T
Sift4G	Benign	0.22	T
Polyphen		0.0020	B
Vest4		0.081
MPC		0.15
ClinPred		0.0027	T
GERP RS		-2.6
Varity_R		0.092
gMVP		0.28
Mutation Taster		=87/13	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: rs6847454; hg19: chr4-126238924; COSMIC: COSV67886468;