9-97853077-C-T

Variant names:

• chr9-97853077-C-T
• rs907576
• ENST00000649253.2:n.4G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000649253.2(PTCSC2):​n.4G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.817 in 152,152 control chromosomes in the GnomAD database, including 51,483 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.82 (51483 hom., cov: 32)
• Consequence: PTCSC2 ENST00000649253.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.485
• Publications: 2 publications found

Genes affected

PTCSC2 (HGNC:44086): (papillary thyroid carcinoma susceptibility candidate 2)

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCSC2	NR_147055.1	n.4G>A		non_coding_transcript_exon_variant	Exon 1 of 11
FOXE1	NM_004473.4	c.-838C>T		upstream_gene_variant		ENST00000375123.5	NP_004464.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOXE1	ENST00000375123.5	c.-838C>T		upstream_gene_variant		6	NM_004473.4	ENSP00000364265.3

Frequencies

GnomAD3 genomes AF: 0.816 AC: 124137 AN: 152036 Hom.: 51424 Cov.: 32

Gnomad AFR AF: 0.943

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.763

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.801

Gnomad FIN AF: 0.831

Gnomad MID AF: 0.812

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.821

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.817 AC: 124248 AN: 152152 Hom.: 51483 Cov.: 32 AF XY: 0.823 AC XY: 61245 AN XY: 74374

African (AFR) AF: 0.943 AC: 39179 AN: 41564

American (AMR) AF: 0.821 AC: 12558 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.763 AC: 2647 AN: 3468

East Asian (EAS) AF: 0.994 AC: 5110 AN: 5142

South Asian (SAS) AF: 0.800 AC: 3858 AN: 4824

European-Finnish (FIN) AF: 0.831 AC: 8802 AN: 10590

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

European-Non Finnish (NFE) AF: 0.730 AC: 49590 AN: 67950

Other (OTH) AF: 0.823 AC: 1738 AN: 2112

Alfa AF: 0.767 Hom.: 5307

Bravo AF: 0.825

Asia WGS AF: 0.917 AC: 3179 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.9
DANN	Benign	0.94
PhyloP100		-0.48
PromoterAI		0.023	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs907576; hg19: chr9-100615359;