chr2-113216213-C-T

Variant names:

• chr2-113216213-C-T
• rs138391311
• NM_003466.4:c.*2320G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003466.4(PAX8):​c.*2320G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000806 in 230,812 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00086 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.547
• Publications: 0 publications found

Genes affected

PAX8 (HGNC:8622): (paired box 8) This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

PAX8-AS1 (HGNC:49271): (PAX8 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00086 (131/152258) while in subpopulation EAS AF = 0.013 (67/5172). AF 95% confidence interval is 0.0105. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 131 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003466.4. 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
	PAX8	NM_003466.4	MANE Select	c.*2320G>A		3_prime_UTR	Exon 12 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.*2397G>A		3_prime_UTR	Exon 12 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.*2397G>A		3_prime_UTR	Exon 10 of 10	NP_039247.1	Q06710-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX8	ENST00000429538.8	TSL:1 MANE Select	c.*2320G>A		3_prime_UTR	Exon 12 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.*2320G>A		3_prime_UTR	Exon 12 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.*2397G>A		3_prime_UTR	Exon 12 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0129

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000700 AC: 55 AN: 78554 Hom.: 0 Cov.: 0 AF XY: 0.000745 AC XY: 27 AN XY: 36228

African (AFR) AF: 0.000267 AC: 1 AN: 3750

American (AMR) AF: 0.00 AC: 0 AN: 2392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4958

East Asian (EAS) AF: 0.00413 AC: 46 AN: 11130

South Asian (SAS) AF: 0.00 AC: 0 AN: 684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 62

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 484

European-Non Finnish (NFE) AF: 0.0000206 AC: 1 AN: 48494

Other (OTH) AF: 0.00106 AC: 7 AN: 6600

GnomAD4 genome AF: 0.000860 AC: 131 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000954 AC XY: 71 AN XY: 74432

African (AFR) AF: 0.000866 AC: 36 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0130 AC: 67 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000555 Hom.: 0

Bravo AF: 0.000880

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hypothyroidism, congenital, nongoitrous, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.63
PhyloP100		-0.55
Mutation Taster		=100/0	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: rs138391311; hg19: chr2-113973790;