chr9-97854301-T-C

Variant names:

• chr9-97854301-T-C
• rs3021523
• NM_004473.4:c.387T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004473.4(FOXE1):​c.387T>C​(p.Leu129Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.763 in 1,610,936 control chromosomes in the GnomAD database, including 473,028 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51150 hom., cov: 31)
  • Exomes 𝑓: 0.76 (421878 hom.)
• Consequence: FOXE1 NM_004473.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0830
• Publications: 28 publications found

Genes affected

FOXE1 (HGNC:3806): (forkhead box E1) This intronless gene encodes a protein that belongs to the forkhead family of transcription factors. Members of this family contain a conserved 100-amino acid DNA-binding 'forkhead' domain. The encoded protein functions as a thyroid transcription factor that plays a role in thyroid morphogenesis. Mutations in this gene are associated with the Bamforth-Lazarus syndrome, and with susceptibility to nonmedullary thyroid cancer-4. [provided by RefSeq, Nov 2016]

FOXE1 Gene-Disease associations (from GenCC):

• Bamforth-Lazarus syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 9-97854301-T-C is Benign according to our data. Variant chr9-97854301-T-C is described in ClinVar as Benign. ClinVar VariationId is 95096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.083 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004473.4. 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
	FOXE1	NM_004473.4	MANE Select	c.387T>C	p.Leu129Leu	synonymous	Exon 1 of 1	NP_004464.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE1	ENST00000375123.5	TSL:6 MANE Select	c.387T>C	p.Leu129Leu	synonymous	Exon 1 of 1	ENSP00000364265.3

Frequencies

GnomAD3 genomes AF: 0.816 AC: 123531 AN: 151478 Hom.: 51096 Cov.: 31

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.761

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.809

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.817

GnomAD2 exomes AF: 0.802 AC: 199316 AN: 248542 AF XY: 0.795

Gnomad AFR exome AF: 0.946

Gnomad AMR exome AF: 0.854

Gnomad ASJ exome AF: 0.767

Gnomad EAS exome AF: 0.998

Gnomad FIN exome AF: 0.818

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.782

GnomAD4 exome AF: 0.758 AC: 1105609 AN: 1459350 Hom.: 421878 Cov.: 68 AF XY: 0.757 AC XY: 549784 AN XY: 726046

African (AFR) AF: 0.949 AC: 31715 AN: 33426

American (AMR) AF: 0.850 AC: 37818 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 19950 AN: 26112

East Asian (EAS) AF: 0.996 AC: 39461 AN: 39606

South Asian (SAS) AF: 0.779 AC: 67057 AN: 86026

European-Finnish (FIN) AF: 0.812 AC: 42717 AN: 52632

Middle Eastern (MID) AF: 0.773 AC: 4460 AN: 5766

European-Non Finnish (NFE) AF: 0.734 AC: 815708 AN: 1110980

Other (OTH) AF: 0.775 AC: 46723 AN: 60306

GnomAD4 genome AF: 0.816 AC: 123634 AN: 151586 Hom.: 51150 Cov.: 31 AF XY: 0.823 AC XY: 60938 AN XY: 74068

African (AFR) AF: 0.940 AC: 38968 AN: 41466

American (AMR) AF: 0.820 AC: 12514 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.761 AC: 2643 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5031 AN: 5062

South Asian (SAS) AF: 0.801 AC: 3856 AN: 4816

European-Finnish (FIN) AF: 0.831 AC: 8688 AN: 10450

Middle Eastern (MID) AF: 0.815 AC: 238 AN: 292

European-Non Finnish (NFE) AF: 0.730 AC: 49441 AN: 67752

Other (OTH) AF: 0.819 AC: 1727 AN: 2108

Alfa AF: 0.756 Hom.: 15992

Bravo AF: 0.824

Asia WGS AF: 0.916 AC: 3150 AN: 3438

EpiCase AF: 0.731

EpiControl AF: 0.742

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Bamforth-Lazarus syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.5
DANN	Benign	0.63
PhyloP100		0.083
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3021523; hg19: chr9-100616583; COSMIC: COSV64300823;