chr4-125448976-A-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS1

The NM_001291303.3(FAT4):c.7966A>C(p.Lys2656Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K2656K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

FAT4
NM_001291303.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 7.20

Publications

0 publications found

Variant links:

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

FAT4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 4-125448976-A-C is Benign according to our data. Variant chr4-125448976-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221915.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000253 (37/1461690) while in subpopulation MID AF = 0.00052 (3/5768). AF 95% confidence interval is 0.000141. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 41. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT4	NM_001291303.3	MANE Select	c.7966A>C	p.Lys2656Gln	missense	Exon 10 of 18	NP_001278232.1	A0A6Q8JR05
FAT4	NM_001438396.1		c.7966A>C	p.Lys2656Gln	missense	Exon 9 of 17	NP_001425325.1
FAT4	NM_001291285.3		c.7966A>C	p.Lys2656Gln	missense	Exon 10 of 18	NP_001278214.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAT4	ENST00000394329.9	TSL:5 MANE Select	c.7966A>C	p.Lys2656Gln	missense	Exon 10 of 18	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5	TSL:1	c.2854A>C	p.Lys952Gln	missense	Exon 9 of 15	ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2		c.2737A>C	p.Lys913Gln	missense	Exon 9 of 17	ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000800

AC:

AN:

249902

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461690

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111902

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.000131

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Anophthalmia-microphthalmia syndrome (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

0.18

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.5

PhyloP100

7.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.29

REVEL

Benign

0.20

Sift

Benign

0.43

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.78

MutPred

0.40

Loss of ubiquitination at K2654 (P = 0.0224)

MVP

0.36

MPC

0.67

ClinPred

0.41

GERP RS

4.5

Varity_R

0.11

gMVP

0.49

Mutation Taster

=69/31

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over