rs9307561

Variant names:

• chr4-125365159-T-C
• rs9307561
• NM_001291303.3:c.5176-33625T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001291303.3(FAT4):​c.5176-33625T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.584 in 152,034 control chromosomes in the GnomAD database, including 25,930 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.58 (25930 hom., cov: 31)
• Consequence: FAT4 NM_001291303.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.5176-33625T>C		intron_variant	Intron 2 of 17	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.5176-33625T>C		intron_variant	Intron 2 of 17	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000674496.2	c.-54-33625T>C		intron_variant	Intron 1 of 16			ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88711 AN: 151918 Hom.: 25886 Cov.: 31

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.558

Gnomad OTH AF: 0.591

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.584 AC: 88808 AN: 152034 Hom.: 25930 Cov.: 31 AF XY: 0.585 AC XY: 43450 AN XY: 74306

African (AFR) AF: 0.621 AC: 25765 AN: 41488

American (AMR) AF: 0.660 AC: 10070 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1786 AN: 3472

East Asian (EAS) AF: 0.539 AC: 2774 AN: 5146

South Asian (SAS) AF: 0.549 AC: 2643 AN: 4816

European-Finnish (FIN) AF: 0.561 AC: 5934 AN: 10584

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.558 AC: 37914 AN: 67954

Other (OTH) AF: 0.595 AC: 1256 AN: 2110

Alfa AF: 0.585 Hom.: 4077

Bravo AF: 0.595

Asia WGS AF: 0.556 AC: 1935 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.29
DANN	Benign	0.34
PhyloP100		-1.0
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: rs9307561; hg19: chr4-126286314;