14-28768762-C-A

Position:

• chr14-28768762-C-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_005249.5(FOXG1):​c.*13C>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.017 in 1,613,930 control chromosomes in the GnomAD database, including 263 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (15 hom., cov: 32)
  • Exomes 𝑓: 0.017 (248 hom.)
• Consequence: FOXG1 NM_005249.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.58

Genes affected

FOXG1 (HGNC:3811): (forkhead box G1) This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]

LINC01551 (HGNC:19828): (long intergenic non-protein coding RNA 1551)

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-28768762-C-A is Benign according to our data. Variant chr14-28768762-C-A is described in ClinVar as [Benign]. Clinvar id is 95263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-28768762-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0128 (1944/152174) while in subpopulation AMR AF= 0.0251 (383/15280). AF 95% confidence interval is 0.023. There are 15 homozygotes in gnomad4. There are 949 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1944 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOXG1	NM_005249.5	c.*13C>A		3_prime_UTR_variant	1/1	ENST00000313071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOXG1	ENST00000313071.7	c.*13C>A		3_prime_UTR_variant	1/1		NM_005249.5	P1
FOXG1	ENST00000706482.1	c.*13C>A		3_prime_UTR_variant	2/2			P1
LINC01551	ENST00000675861.1	n.374+2749C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1944 AN: 152056 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0252

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.0164 AC: 4120 AN: 251124 Hom.: 53 AF XY: 0.0152 AC XY: 2066 AN XY: 135860

Gnomad AFR exome AF: 0.00324

Gnomad AMR exome AF: 0.0421

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00621

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.0180

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0174 AC: 25436 AN: 1461756 Hom.: 248 Cov.: 33 AF XY: 0.0169 AC XY: 12312 AN XY: 727172

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.0388

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00544

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0128 AC: 1944 AN: 152174 Hom.: 15 Cov.: 32 AF XY: 0.0128 AC XY: 949 AN XY: 74386

Gnomad4 AFR AF: 0.00352

Gnomad4 AMR AF: 0.0251

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0181

Gnomad4 OTH AF: 0.00997

Alfa AF: 0.0146 Hom.: 7

Bravo AF: 0.0142

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.90

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: rs151157846; hg19: chr14-29237968;