NM_001291303.3:c.7199+3876A>G

Variant names:

• chr4-125438301-A-G
• rs1395241
• NM_001291303.3:c.7199+3876A>G

Variant summary

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

The NM_001291303.3(FAT4):​c.7199+3876A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,962 control chromosomes in the GnomAD database, including 13,083 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 0.41 (13083 hom., cov: 32)
• Consequence: FAT4 NM_001291303.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179
• Publications: 7 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.7199+3876A>G		intron_variant	Intron 8 of 17	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.7199+3876A>G		intron_variant	Intron 8 of 17	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000335110.5	c.2093+3876A>G		intron_variant	Intron 7 of 14	1		ENSP00000335169.5
FAT4	ENST00000674496.2	c.1970+3876A>G		intron_variant	Intron 7 of 16			ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62134 AN: 151844 Hom.: 13076 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.415

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

GnomAD4 genome AF: 0.409 AC: 62154 AN: 151962 Hom.: 13083 Cov.: 32 AF XY: 0.409 AC XY: 30401 AN XY: 74262

African (AFR) AF: 0.327 AC: 13570 AN: 41444

American (AMR) AF: 0.393 AC: 5987 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1166 AN: 3464

East Asian (EAS) AF: 0.286 AC: 1478 AN: 5166

South Asian (SAS) AF: 0.286 AC: 1379 AN: 4820

European-Finnish (FIN) AF: 0.539 AC: 5689 AN: 10552

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.463 AC: 31453 AN: 67954

Other (OTH) AF: 0.411 AC: 869 AN: 2112

Alfa AF: 0.430 Hom.: 18340

Bravo AF: 0.400

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.43
DANN	Benign	0.58
PhyloP100		-0.18
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: rs1395241; hg19: chr4-126359456;