7-122302795-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001024613.4(FEZF1):c.1069+4T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0323 in 1,612,876 control chromosomes in the GnomAD database, including 1,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (70 hom., cov: 32)
  • Exomes 𝑓: 0.033 (952 hom.)
• Consequence: FEZF1 NM_001024613.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001987
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.433

Genes affected

FEZF1 (HGNC:22788): (FEZ family zinc finger 1) This gene encodes a transcriptional repressor that belongs to the zinc finger double domain protein family. The encoded protein is thought to play a role in the embryonic migration of gonadotropin-releasing hormone neurons into the brain. Mutations in this gene are associated with hypogonadotropic hypogonadism-22 with anosmia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-122302795-A-G is Benign according to our data. Variant chr7-122302795-A-G is described in ClinVar as [Benign]. Clinvar id is 1267416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0257 (3899/151902) while in subpopulation NFE AF= 0.0369 (2509/67996). AF 95% confidence interval is 0.0357. There are 70 homozygotes in gnomad4. There are 1946 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FEZF1	NM_001024613.4	c.1069+4T>C		splice_donor_region_variant, intron_variant		ENST00000442488.7
FEZF1	NM_001160264.2	c.919+4T>C		splice_donor_region_variant, intron_variant
FEZF1	XM_005250337.4	c.1069+4T>C		splice_donor_region_variant, intron_variant
FEZF1	XM_011516202.3	c.919+4T>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FEZF1	ENST00000442488.7	c.1069+4T>C		splice_donor_region_variant, intron_variant		1	NM_001024613.4	P2
FEZF1	ENST00000427185.2	c.919+4T>C		splice_donor_region_variant, intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3900 AN: 151784 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00710

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00561

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.0269 AC: 6764 AN: 251342 Hom.: 126 AF XY: 0.0271 AC XY: 3680 AN XY: 135848

Gnomad AFR exome AF: 0.00603

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00602

Gnomad FIN exome AF: 0.0505

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0330 AC: 48257 AN: 1460974 Hom.: 952 Cov.: 35 AF XY: 0.0322 AC XY: 23428 AN XY: 726864

Gnomad4 AFR exome AF: 0.00666

Gnomad4 AMR exome AF: 0.0162

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00593

Gnomad4 FIN exome AF: 0.0488

Gnomad4 NFE exome AF: 0.0378

Gnomad4 OTH exome AF: 0.0286

GnomAD4 genome AF: 0.0257 AC: 3899 AN: 151902 Hom.: 70 Cov.: 32 AF XY: 0.0262 AC XY: 1946 AN XY: 74202

Gnomad4 AFR AF: 0.00708

Gnomad4 AMR AF: 0.0258

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00541

Gnomad4 FIN AF: 0.0529

Gnomad4 NFE AF: 0.0369

Gnomad4 OTH AF: 0.0256

Alfa AF: 0.0302 Hom.: 36

Bravo AF: 0.0232

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0377

EpiControl AF: 0.0370

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	14
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs117528546; hg19: chr7-121942849;