4-125449031-A-T

Position:

• chr4-125449031-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001291303.3(FAT4):​c.8021A>T​(p.Asp2674Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,802 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (6 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 9.14

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08642647).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00187 (284/152214) while in subpopulation NFE AF= 0.00347 (236/68012). AF 95% confidence interval is 0.00311. There are 0 homozygotes in gnomad4. There are 113 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.8021A>T	p.Asp2674Val	missense_variant	10/18	ENST00000394329.9	NP_001278232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAT4	ENST00000394329.9	c.8021A>T	p.Asp2674Val	missense_variant	10/18	5	NM_001291303.3	ENSP00000377862.4
FAT4	ENST00000335110.5	c.2909A>T	p.Asp970Val	missense_variant	9/15	1		ENSP00000335169.5
FAT4	ENST00000674496.2	c.2792A>T	p.Asp931Val	missense_variant	9/17			ENSP00000501473.2

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00347

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00138 AC: 345 AN: 249764 Hom.: 0 AF XY: 0.00131 AC XY: 178 AN XY: 135400

Gnomad AFR exome AF: 0.000705

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00291 AC: 4255 AN: 1461588 Hom.: 6 Cov.: 41 AF XY: 0.00288 AC XY: 2092 AN XY: 727092

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000615

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74458

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00347

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00190

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00122 AC: 148

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2018	The D2672V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D2672V variant is observed in 315/126102 (0.25%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). The D2672V variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. GeneDx interprets D2672V as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	The FAT4 c.8015A>T; p.Asp2672Val variant (rs138655269), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 420323). This variant is found in the non-Finnish European population with an overall allele frequency of 0.25% (324/128362 alleles) in the Genome Aggregation Database. The aspartate at codon 2672 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.396). Due to limited information, the clinical significance of the p.Asp2672Val variant is uncertain at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Van Maldergem syndrome 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Mar 01, 2021	The FAT4 c.8015A>T (p.Asp2672Val) missense variant is located in exon 10, and results in a single amino acid substitution from an aspartic acid to a valine. This variant was detected in the compound heterozygous state in an individual with Van Maldergem syndrome 2; this individual was also reported to have diploid/triploid mosaicism (ClinVar entry from Undiagnosed Diseases Network). The variant was also described in the homozygous state in a 3 year-old male with suspected Van Maldergem syndrome; he also had compound heterozygous variants in CYP21A2 and was diagnosed with congenital adrenal hyperplasia (PMID: 31384091). FAT4 c.8015A>T (p.Asp2672Val) is present in human population databases (allele frequency 383 alleles/281150 total alleles: 0.001). Due to the limited information regarding this variant, it is classified as a VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Nov 16, 2016	- -

FAT4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 02, 2022

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	0.13
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.40
Sift	Benign	0.47	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.77
MVP		0.63
MPC		0.77
ClinPred		0.046	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs138655269; hg19: chr4-126370186;