chr9-97853378-G-C

Variant names:

• chr9-97853378-G-C
• rs7849497
• NM_004473.4:c.-537G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004473.4(FOXE1):​c.-537G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 152,740 control chromosomes in the GnomAD database, including 51,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51399 hom., cov: 34)
  • Exomes 𝑓: 0.74 (147 hom.)
• Consequence: FOXE1 NM_004473.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.337
• Publications: 9 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-97853378-G-C is Benign according to our data. Variant chr9-97853378-G-C is described in ClinVar as Benign. ClinVar VariationId is 1271089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.-537G>C		5_prime_UTR	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.-537G>C		5_prime_UTR	Exon 1 of 1	ENSP00000364265.3	O00358

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124088 AN: 152108 Hom.: 51343 Cov.: 34

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.812

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.819

GnomAD4 exome AF: 0.739 AC: 383 AN: 518 Hom.: 147 Cov.: 0 AF XY: 0.741 AC XY: 237 AN XY: 320

African (AFR) AF: 1.00 AC: 24 AN: 24

American (AMR) AF: 0.857 AC: 12 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.800 AC: 8 AN: 10

East Asian (EAS) AF: 1.00 AC: 12 AN: 12

South Asian (SAS) AF: 0.667 AC: 16 AN: 24

European-Finnish (FIN) AF: 0.800 AC: 16 AN: 20

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.701 AC: 269 AN: 384

Other (OTH) AF: 0.857 AC: 24 AN: 28

GnomAD4 genome AF: 0.816 AC: 124195 AN: 152222 Hom.: 51399 Cov.: 34 AF XY: 0.823 AC XY: 61228 AN XY: 74420

African (AFR) AF: 0.940 AC: 39091 AN: 41576

American (AMR) AF: 0.820 AC: 12554 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2650 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5111 AN: 5142

South Asian (SAS) AF: 0.800 AC: 3864 AN: 4828

European-Finnish (FIN) AF: 0.831 AC: 8816 AN: 10612

Middle Eastern (MID) AF: 0.818 AC: 239 AN: 292

European-Non Finnish (NFE) AF: 0.730 AC: 49605 AN: 67968

Other (OTH) AF: 0.821 AC: 1737 AN: 2116

Alfa AF: 0.772 Hom.: 5715

Bravo AF: 0.824

Asia WGS AF: 0.916 AC: 3182 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.0
DANN	Benign	0.61
PhyloP100		-0.34
PromoterAI		-0.051	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs7849497; hg19: chr9-100615660;