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:7
• 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):

• FAT4-related neurodevelopmental disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	NM_001291303.3	MANE Select	c.6733G>A	p.Val2245Ile	missense	Exon 6 of 18	NP_001278232.1	A0A6Q8JR05
	FAT4	NM_001438396.1		c.6733G>A	p.Val2245Ile	missense	Exon 5 of 17	NP_001425325.1
	FAT4	NM_001291285.3		c.6733G>A	p.Val2245Ile	missense	Exon 6 of 18	NP_001278214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAT4	ENST00000394329.9	TSL:5 MANE Select	c.6733G>A	p.Val2245Ile	missense	Exon 6 of 18	ENSP00000377862.4	A0A6Q8JR05
	FAT4	ENST00000335110.5	TSL:1	c.1627G>A	p.Val543Ile	missense	Exon 5 of 15	ENSP00000335169.5	Q6V0I7-2
	FAT4	ENST00000674496.2		c.1504G>A	p.Val502Ile	missense	Exon 5 of 17	ENSP00000501473.2	A0A7P0T1I0

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	FAT4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.7
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.30	N
REVEL	Uncertain	0.33
Sift	Benign	0.12	T
Sift4G	Uncertain	0.013	D
Polyphen		1.0	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;