9-97854657-C-G

Variant names:

• chr9-97854657-C-G
• rs538912281
• NM_004473.4:c.743C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004473.4(FOXE1):​c.743C>G​(p.Ala248Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,402,532 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (11 hom.)
• Consequence: FOXE1 NM_004473.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:3
• Conservation: PhyloP100: -0.495
• Publications: 16 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074782073).
• BP6: Variant 9-97854657-C-G is Benign according to our data. Variant chr9-97854657-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208453.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE1	NM_004473.4	MANE Select	c.743C>G	p.Ala248Gly	missense	Exon 1 of 1	NP_004464.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOXE1	ENST00000375123.5	TSL:6 MANE Select	c.743C>G	p.Ala248Gly	missense	Exon 1 of 1	ENSP00000364265.3

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 429 AN: 151700 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000860

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00197 AC: 59 AN: 30012 AF XY: 0.00188

Gnomad AFR exome AF: 0.00220

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00336

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000526

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00431 AC: 5396 AN: 1250724 Hom.: 11 Cov.: 50 AF XY: 0.00431 AC XY: 2642 AN XY: 613256

African (AFR) AF: 0.000455 AC: 11 AN: 24200

American (AMR) AF: 0.00185 AC: 27 AN: 14562

Ashkenazi Jewish (ASJ) AF: 0.00425 AC: 80 AN: 18816

East Asian (EAS) AF: 0.00 AC: 0 AN: 27864

South Asian (SAS) AF: 0.000297 AC: 18 AN: 60564

European-Finnish (FIN) AF: 0.00132 AC: 40 AN: 30404

Middle Eastern (MID) AF: 0.00442 AC: 16 AN: 3620

European-Non Finnish (NFE) AF: 0.00494 AC: 5037 AN: 1019394

Other (OTH) AF: 0.00326 AC: 167 AN: 51300

GnomAD4 genome AF: 0.00283 AC: 429 AN: 151808 Hom.: 2 Cov.: 33 AF XY: 0.00284 AC XY: 211 AN XY: 74192

African (AFR) AF: 0.000844 AC: 35 AN: 41488

American (AMR) AF: 0.00223 AC: 34 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000860 AC: 9 AN: 10462

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00491 AC: 333 AN: 67864

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000479 Hom.: 0

Bravo AF: 0.00266

ExAC AF: 0.00124 AC: 90

Asia WGS AF: 0.000295 AC: 1 AN: 3410

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Bamforth-Lazarus syndrome (2)
-	1	-	Bamforth-Lazarus syndrome;C4225293:Thyroid cancer, nonmedullary, 4 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
1	-	-	Thyroid cancer, nonmedullary, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.49
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.41	N
REVEL	Pathogenic	0.66
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.65
MVP		0.68
ClinPred		0.024	T
GERP RS		2.6
Varity_R		0.063
gMVP		0.23
Mutation Taster		=86/14	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: rs538912281; hg19: chr9-100616939; COSMIC: COSV64300311;