rs144506470

Positions:

• chr4-125451570-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001291303.3(FAT4):​c.10560G>A​(p.Met3520Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000559 in 1,614,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: FAT4 NM_001291303.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 4.07

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048460364).
• BP6: Variant 4-125451570-G-A is Benign according to our data. Variant chr4-125451570-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522864.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000532 (81/152288) while in subpopulation NFE AF= 0.00075 (51/68020). AF 95% confidence interval is 0.000586. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAT4	NM_001291303.3	c.10560G>A	p.Met3520Ile	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.10560G>A	p.Met3520Ile	missense_variant	10/18	5	NM_001291303.3	ENSP00000377862	P1
FAT4	ENST00000335110.5	c.5448G>A	p.Met1816Ile	missense_variant	9/15	1		ENSP00000335169
FAT4	ENST00000674496.2	c.5331G>A	p.Met1777Ile	missense_variant	9/17			ENSP00000501473

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000633 AC: 159 AN: 251220 Hom.: 0 AF XY: 0.000619 AC XY: 84 AN XY: 135776

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000562 AC: 821 AN: 1461872 Hom.: 1 Cov.: 56 AF XY: 0.000557 AC XY: 405 AN XY: 727238

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000634

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74464

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.000616

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000601 AC: 73

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -

Van Maldergem syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.068	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.0058
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.087
Sift	Benign	0.40	T;T
Sift4G	Uncertain	0.021	D;D
Polyphen		0.053	B;B
Vest4		0.53
MutPred		0.51		Loss of disorder (P = 0.0422);.;
MVP		0.32
MPC		0.19
ClinPred		0.0092	T
GERP RS		3.5
Varity_R		0.060
gMVP		0.22

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: rs144506470; hg19: chr4-126372725; COSMIC: COSV100627451; COSMIC: COSV100627451;