rs727503933

Variant names:

• chr14-28767485-C-A
• rs727503933
• NM_005249.5:c.206C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-28767485-C-A
• chr14-28767485-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005249.5(FOXG1):​c.206C>A​(p.Pro69Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000338 in 1,054,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P69L) has been classified as Likely benign. The gene FOXG1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: FOXG1 NM_005249.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.665
• Publications: 1 publications found

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

Specifications for FOXG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04875952).
• BP6: Variant 14-28767485-C-A is Benign according to our data. Variant chr14-28767485-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167089.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 = 0.000528 (76/143992) while in subpopulation AFR AF = 0.00148 (59/39868). AF 95% confidence interval is 0.00118. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 76 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005249.5. 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
	FOXG1	NM_005249.5	MANE Select	c.206C>A	p.Pro69Gln	missense	Exon 1 of 1	NP_005240.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXG1	ENST00000313071.7	TSL:6 MANE Select	c.206C>A	p.Pro69Gln	missense	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.206C>A	p.Pro69Gln	missense	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1472C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000528 AC: 76 AN: 143904 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000137

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: 0.000230

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 11 AN: 62992 AF XY: 0.000165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000429

Gnomad ASJ exome AF: 0.000184

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000445

Gnomad NFE exome AF: 0.0000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000309 AC: 281 AN: 910748 Hom.: 0 Cov.: 18 AF XY: 0.000289 AC XY: 127 AN XY: 440160

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00165 AC: 30 AN: 18232

American (AMR) AF: 0.000479 AC: 8 AN: 16690

Ashkenazi Jewish (ASJ) AF: 0.000169 AC: 2 AN: 11824

East Asian (EAS) AF: 0.000354 AC: 4 AN: 11310

South Asian (SAS) AF: 0.000360 AC: 12 AN: 33322

European-Finnish (FIN) AF: 0.000219 AC: 3 AN: 13688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2174

European-Non Finnish (NFE) AF: 0.000266 AC: 205 AN: 771288

Other (OTH) AF: 0.000528 AC: 17 AN: 32220

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000528 AC: 76 AN: 143992 Hom.: 0 Cov.: 31 AF XY: 0.000500 AC XY: 35 AN XY: 70062

African (AFR) AF: 0.00148 AC: 59 AN: 39868

American (AMR) AF: 0.000137 AC: 2 AN: 14578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3322

East Asian (EAS) AF: 0.00 AC: 0 AN: 4932

South Asian (SAS) AF: 0.00 AC: 0 AN: 4662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000230 AC: 15 AN: 65178

Other (OTH) AF: 0.00 AC: 0 AN: 1984

Alfa AF: 0.000674 Hom.: 0

Bravo AF: 0.000567

ExAC AF: 0.0000724 AC: 3

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FOXG1 disorder (1)
-	-	1	FOXG1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.33	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.67
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.038
Sift	Benign	0.31	T
Sift4G	Benign	0.14	T
Polyphen		0.056	B
Vest4		0.21
MutPred		0.30		Gain of catalytic residue at P65 (P = 5e-04)
MVP		0.040
ClinPred		0.023	T
GERP RS		-1.2
Varity_R		0.077
gMVP		0.34
Mutation Taster		=94/6	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: rs727503933; hg19: chr14-29236691; COSMIC: COSV57394806; COSMIC: COSV57394806;