3-62371330-T-C

Variant names:

• chr3-62371330-T-C
• rs201890958
• NM_018008.4:c.1007A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018008.4(FEZF2):​c.1007A>G​(p.Asn336Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FEZF2 NM_018008.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86
• Publications: 1 publications found

Genes affected

FEZF2 (HGNC:13506): (FEZ family zinc finger 2) Predicted to enable transcription cis-regulatory region binding activity. Predicted to be involved in positive regulation of transcription, DNA-templated. Predicted to act upstream of or within several processes, including negative regulation of transcription by RNA polymerase II; nervous system development; and regulation of neuron differentiation. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FEZF2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24325311).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FEZF2	NM_018008.4	c.1007A>G	p.Asn336Ser	missense_variant	Exon 4 of 5	ENST00000283268.8	NP_060478.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FEZF2	ENST00000283268.8	c.1007A>G	p.Asn336Ser	missense_variant	Exon 4 of 5	1	NM_018008.4	ENSP00000283268.3
FEZF2	ENST00000475839.1	c.1007A>G	p.Asn336Ser	missense_variant	Exon 3 of 4	1		ENSP00000418804.1
FEZF2	ENST00000486811.5	c.1007A>G	p.Asn336Ser	missense_variant	Exon 5 of 6	5		ENSP00000418589.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251268 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461798 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111950

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74476

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000261 AC: 4 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1007A>G (p.N336S) alteration is located in exon 4 (coding exon 3) of the FEZF2 gene. This alteration results from a A to G substitution at nucleotide position 1007, causing the asparagine (N) at amino acid position 336 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	.;.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-0.42	N;N;N
PhyloP100		4.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.094	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.47
MVP		0.30
MPC		2.4
ClinPred		0.46	T
GERP RS		6.2
Varity_R		0.28
gMVP		0.72
Mutation Taster		=29/71	disease causing

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: rs201890958; hg19: chr3-62357005;