rs769410384

Variant names:

• chr14-28767438-C-T
• rs769410384
• NM_005249.5:c.159C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-28767438-C-T
• chr14-28767438-C-A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_005249.5(FOXG1):​c.159C>T​(p.His53His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 146,160 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FOXG1 NM_005249.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.872
• Publications: 0 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

Our verdict: Benign. The variant received -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 14-28767438-C-T is Benign according to our data. Variant chr14-28767438-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 487208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.872 with no splicing effect.

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.159C>T	p.His53His	synonymous	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.159C>T	p.His53His	synonymous	Exon 1 of 1	ENSP00000339004.3	P55316
	FOXG1	ENST00000706482.1		c.159C>T	p.His53His	synonymous	Exon 2 of 2	ENSP00000516406.1	P55316
	LINC01551	ENST00000675861.1		n.374+1425C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146160 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

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: 0.0000315 AC: 3 AN: 95302 AF XY: 0.0000376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000990

Gnomad NFE exome AF: 0.0000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000167 AC: 19 AN: 1136432 Hom.: 0 Cov.: 26 AF XY: 0.0000143 AC XY: 8 AN XY: 558300

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

African (AFR) AF: 0.00 AC: 0 AN: 22830

American (AMR) AF: 0.0000430 AC: 1 AN: 23274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16848

East Asian (EAS) AF: 0.00 AC: 0 AN: 20888

South Asian (SAS) AF: 0.0000543 AC: 3 AN: 55230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3204

European-Non Finnish (NFE) AF: 0.0000152 AC: 14 AN: 920212

Other (OTH) AF: 0.0000237 AC: 1 AN: 42256

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000039635), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146160 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 1 AN XY: 71066

African (AFR) AF: 0.00 AC: 0 AN: 40602

American (AMR) AF: 0.0000679 AC: 1 AN: 14736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.00 AC: 0 AN: 5022

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65726

Other (OTH) AF: 0.00 AC: 0 AN: 2010

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rett syndrome, congenital variant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	9.4
DANN	Benign	0.72
PhyloP100		0.87

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: rs769410384; hg19: chr14-29236644;