rs112971995

Variant names:

• chr4-125415696-G-A
• rs112971995
• NM_001291303.3:c.6733G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-125415696-G-A
• chr4-125415696-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291303.3(FAT4):​c.6733G>A​(p.Val2245Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000766 in 1,613,932 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (8 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.70
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006260574).
• BP6: Variant 4-125415696-G-A is Benign according to our data. Variant chr4-125415696-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00392 (596/152202) while in subpopulation AFR AF = 0.0136 (564/41542). AF 95% confidence interval is 0.0126. There are 5 homozygotes in GnomAd4. There are 293 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.6733G>A	p.Val2245Ile	missense_variant	Exon 6 of 18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.6733G>A	p.Val2245Ile	missense_variant	Exon 6 of 18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000335110.5	c.1627G>A	p.Val543Ile	missense_variant	Exon 5 of 15	1		ENSP00000335169.5
FAT4	ENST00000674496.2	c.1504G>A	p.Val502Ile	missense_variant	Exon 5 of 17			ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152084 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 251078 AF XY: 0.000781

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000438 AC: 640 AN: 1461730 Hom.: 8 Cov.: 34 AF XY: 0.000378 AC XY: 275 AN XY: 727174

African (AFR) AF: 0.0155 AC: 518 AN: 33474

American (AMR) AF: 0.000537 AC: 24 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111920

Other (OTH) AF: 0.00118 AC: 71 AN: 60388

GnomAD4 genome AF: 0.00392 AC: 596 AN: 152202 Hom.: 5 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74406

African (AFR) AF: 0.0136 AC: 564 AN: 41542

American (AMR) AF: 0.00164 AC: 25 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00158 Hom.: 8

Bravo AF: 0.00448

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FAT4: BP4, BS1, BS2 -

Jun 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FAT4-related disorder Benign:1

Apr 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.073	T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0063	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		6.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.30	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.29
MVP		0.46
MPC		0.59
ClinPred		0.035	T
GERP RS		4.6
Varity_R		0.039
gMVP		0.24
Mutation Taster		=95/5	polymorphism

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: rs112971995; hg19: chr4-126336851;