dbSNP rs587777724: FAT4:p.Thr2349_Ile2350insGlyThr (chr4-125434258-G-GACTGGA) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM4PP3PP5

The NM_001291303.3(FAT4):c.7041_7046dupTGGAAC(p.Thr2349_Ile2350insGlyThr) variant causes a disruptive inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FAT4
NM_001291303.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.96

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):

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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001291303.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 4-125434258-G-GACTGGA is Pathogenic according to our data. Variant chr4-125434258-G-GACTGGA is described in ClinVar as Pathogenic. ClinVar VariationId is 156109.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3 link	c.7041_7046dupTGGAAC	p.Thr2349_Ile2350insGlyThr	disruptive_inframe_insertion	Exon 8 of 18	ENST00000394329.9	NP_001278232.1	Q6V0I7A0A6Q8JR05X2G5I7B3KU84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAT4	ENST00000394329.9 link	c.7041_7046dupTGGAAC	p.Thr2349_Ile2350insGlyThr	disruptive_inframe_insertion	Exon 8 of 18	5	NM_001291303.3	ENSP00000377862.4	A0A6Q8JR05
FAT4	ENST00000335110.5 link	c.1935_1940dupTGGAAC	p.Thr647_Ile648insGlyThr	disruptive_inframe_insertion	Exon 7 of 15	1		ENSP00000335169.5	Q6V0I7-2
FAT4	ENST00000674496.2 link	c.1812_1817dupTGGAAC	p.Thr606_Ile607insGlyThr	disruptive_inframe_insertion	Exon 7 of 17			ENSP00000501473.2	A0A7P0T1I0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460222

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

85978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111174

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hennekam lymphangiectasia-lymphedema syndrome 2

Pathogenic:1

Sep 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.0

Mutation Taster

=58/42

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over