4-125319355-T-C

Variant names:

• chr4-125319355-T-C
• rs2940779
• NM_001291303.3:c.2944T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001291303.3(FAT4):​c.2944T>C​(p.Leu982Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,612,446 control chromosomes in the GnomAD database, including 405,804 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42865 hom., cov: 32)
  • Exomes 𝑓: 0.70 (362939 hom.)
• Consequence: FAT4 NM_001291303.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.103
• Publications: 26 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):

• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 4-125319355-T-C is Benign according to our data. Variant chr4-125319355-T-C is described in ClinVar as Benign. ClinVar VariationId is 380793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.878 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.2944T>C	p.Leu982Leu	synonymous	Exon 2 of 18	NP_001278232.1
	FAT4	NM_001438396.1		c.2944T>C	p.Leu982Leu	synonymous	Exon 1 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.2944T>C	p.Leu982Leu	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.2944T>C	p.Leu982Leu	synonymous	Exon 2 of 18	ENSP00000377862.4
	FAT4	ENST00000674496.2		c.-55+3378T>C		intron	N/A	ENSP00000501473.2
	FAT4	ENST00000678072.1		n.550T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.743 AC: 112857 AN: 151974 Hom.: 42797 Cov.: 32

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.731

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.708

Gnomad OTH AF: 0.737

GnomAD2 exomes AF: 0.694 AC: 172971 AN: 249100 AF XY: 0.695

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.576

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.690

GnomAD4 exome AF: 0.703 AC: 1026299 AN: 1460354 Hom.: 362939 Cov.: 38 AF XY: 0.704 AC XY: 511406 AN XY: 726632

African (AFR) AF: 0.897 AC: 30014 AN: 33462

American (AMR) AF: 0.703 AC: 31423 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 19214 AN: 26136

East Asian (EAS) AF: 0.486 AC: 19306 AN: 39692

South Asian (SAS) AF: 0.747 AC: 64460 AN: 86238

European-Finnish (FIN) AF: 0.581 AC: 30803 AN: 53002

Middle Eastern (MID) AF: 0.728 AC: 4199 AN: 5768

European-Non Finnish (NFE) AF: 0.706 AC: 784330 AN: 1110972

Other (OTH) AF: 0.705 AC: 42550 AN: 60362

GnomAD4 genome AF: 0.743 AC: 112984 AN: 152092 Hom.: 42865 Cov.: 32 AF XY: 0.735 AC XY: 54599 AN XY: 74318

African (AFR) AF: 0.886 AC: 36779 AN: 41520

American (AMR) AF: 0.731 AC: 11171 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 2532 AN: 3466

East Asian (EAS) AF: 0.473 AC: 2444 AN: 5162

South Asian (SAS) AF: 0.727 AC: 3506 AN: 4820

European-Finnish (FIN) AF: 0.573 AC: 6043 AN: 10552

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.708 AC: 48104 AN: 67964

Other (OTH) AF: 0.740 AC: 1562 AN: 2112

Alfa AF: 0.717 Hom.: 180914

Bravo AF: 0.755

Asia WGS AF: 0.670 AC: 2332 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.706

ClinVar

ClinVar submissions as Germline

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	-0.76
CADD	Benign	3.1
DANN	Benign	0.65
PhyloP100		0.10
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: rs2940779; hg19: chr4-126240510; COSMIC: COSV67882321;