rs2710555

Variant names:

• chr4-125320716-C-T
• rs2710555
• NM_001291303.3:c.4305C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001291303.3(FAT4):​c.4305C>T​(p.Ile1435Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.704 in 1,613,428 control chromosomes in the GnomAD database, including 403,225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I1435I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.73 (41728 hom., cov: 33)
  • Exomes 𝑓: 0.70 (361497 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.852
• Publications: 22 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 4-125320716-C-T is Benign according to our data. Variant chr4-125320716-C-T is described in ClinVar as Benign. ClinVar VariationId is 377855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.852 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.849 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.4305C>T	p.Ile1435Ile	synonymous	Exon 2 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.4305C>T	p.Ile1435Ile	synonymous	Exon 1 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.4305C>T	p.Ile1435Ile	synonymous	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.4305C>T	p.Ile1435Ile	synonymous	Exon 2 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000674496.2		c.-55+4739C>T		intron	N/A	ENSP00000501473.2	A0A7P0T1I0
	FAT4	ENST00000678072.1		n.1911C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111548 AN: 152058 Hom.: 41663 Cov.: 33

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.696

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.707

Gnomad OTH AF: 0.731

GnomAD2 exomes AF: 0.691 AC: 172243 AN: 249316 AF XY: 0.692

Gnomad AFR exome AF: 0.861

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.454

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.701 AC: 1024607 AN: 1461252 Hom.: 361497 Cov.: 48 AF XY: 0.702 AC XY: 510616 AN XY: 726978

African (AFR) AF: 0.865 AC: 28958 AN: 33470

American (AMR) AF: 0.700 AC: 31327 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 19211 AN: 26134

East Asian (EAS) AF: 0.468 AC: 18591 AN: 39692

South Asian (SAS) AF: 0.747 AC: 64401 AN: 86240

European-Finnish (FIN) AF: 0.581 AC: 31027 AN: 53406

Middle Eastern (MID) AF: 0.726 AC: 4183 AN: 5764

European-Non Finnish (NFE) AF: 0.706 AC: 784530 AN: 1111444

Other (OTH) AF: 0.702 AC: 42379 AN: 60378

GnomAD4 genome AF: 0.734 AC: 111672 AN: 152176 Hom.: 41728 Cov.: 33 AF XY: 0.726 AC XY: 53989 AN XY: 74360

African (AFR) AF: 0.856 AC: 35571 AN: 41534

American (AMR) AF: 0.726 AC: 11116 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2538 AN: 3472

East Asian (EAS) AF: 0.461 AC: 2387 AN: 5174

South Asian (SAS) AF: 0.729 AC: 3500 AN: 4804

European-Finnish (FIN) AF: 0.573 AC: 6054 AN: 10562

Middle Eastern (MID) AF: 0.705 AC: 206 AN: 292

European-Non Finnish (NFE) AF: 0.707 AC: 48117 AN: 68012

Other (OTH) AF: 0.733 AC: 1548 AN: 2112

Alfa AF: 0.720 Hom.: 72806

Bravo AF: 0.744

Asia WGS AF: 0.663 AC: 2309 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.706

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
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.5
DANN	Benign	0.71
PhyloP100		0.85
Mutation Taster		=100/0	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: rs2710555; hg19: chr4-126241871; COSMIC: COSV67882328;