chr4-125451820-A-C

Variant names:

• chr4-125451820-A-C
• rs76491994
• NM_001291303.3:c.10810A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291303.3(FAT4):​c.10810A>C​(p.Ile3604Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,614,138 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (205 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.97
• Publications: 17 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=0.0034600794).
• BP6: Variant 4-125451820-A-C is Benign according to our data. Variant chr4-125451820-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00999 (1522/152288) while in subpopulation EAS AF = 0.0276 (143/5178). AF 95% confidence interval is 0.0239. There are 16 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.10810A>C	p.Ile3604Leu	missense	Exon 10 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.10810A>C	p.Ile3604Leu	missense	Exon 9 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.10810A>C	p.Ile3604Leu	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.10810A>C	p.Ile3604Leu	missense	Exon 10 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.5698A>C	p.Ile1900Leu	missense	Exon 9 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.5581A>C	p.Ile1861Leu	missense	Exon 9 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes AF: 0.00998 AC: 1519 AN: 152170 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00982

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.0120 AC: 3013 AN: 250644 AF XY: 0.0119

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0299

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0142 AC: 20814 AN: 1461850 Hom.: 205 Cov.: 71 AF XY: 0.0140 AC XY: 10180 AN XY: 727230

African (AFR) AF: 0.00203 AC: 68 AN: 33480

American (AMR) AF: 0.0101 AC: 452 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26136

East Asian (EAS) AF: 0.0206 AC: 817 AN: 39700

South Asian (SAS) AF: 0.00657 AC: 567 AN: 86258

European-Finnish (FIN) AF: 0.0168 AC: 896 AN: 53406

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0155 AC: 17275 AN: 1111982

Other (OTH) AF: 0.0112 AC: 679 AN: 60396

GnomAD4 genome AF: 0.00999 AC: 1522 AN: 152288 Hom.: 16 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74464

African (AFR) AF: 0.00257 AC: 107 AN: 41562

American (AMR) AF: 0.0101 AC: 154 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5178

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4820

European-Finnish (FIN) AF: 0.0154 AC: 163 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0132 AC: 896 AN: 68020

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0128 Hom.: 59

Bravo AF: 0.00918

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0140 AC: 120

ExAC AF: 0.0112 AC: 1357

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.0126

EpiControl AF: 0.0132

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Van Maldergem syndrome 2;C4014939:Hennekam lymphangiectasia-lymphedema syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.064
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.014	D
Polyphen		0.27	B
Vest4		0.22
MPC		0.41
ClinPred		0.011	T
GERP RS		0.80
Varity_R		0.32
gMVP		0.45
Mutation Taster		=88/12	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: rs76491994; hg19: chr4-126372975; COSMIC: COSV58691157;