2-113216768-C-T

Variant names:

• chr2-113216768-C-T
• rs144041400
• NM_003466.4:c.*1765G>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.*1765G>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 0.0118 in 228,106 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.011 (16 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.938
• 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=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0122 (1861/152300) while in subpopulation NFE AF = 0.0171 (1160/68016). AF 95% confidence interval is 0.0162. There are 16 homozygotes in GnomAd4. There are 967 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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 1861 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.*1765G>A		3_prime_UTR	Exon 12 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.*1842G>A		3_prime_UTR	Exon 12 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.*1842G>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.*1765G>A		3_prime_UTR	Exon 12 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.*1765G>A		3_prime_UTR	Exon 12 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.*1842G>A		3_prime_UTR	Exon 12 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1859 AN: 152182 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0170

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0110 AC: 835 AN: 75806 Hom.: 16 Cov.: 0 AF XY: 0.0108 AC XY: 377 AN XY: 34906

African (AFR) AF: 0.000837 AC: 3 AN: 3584

American (AMR) AF: 0.00869 AC: 20 AN: 2302

Ashkenazi Jewish (ASJ) AF: 0.00725 AC: 35 AN: 4826

East Asian (EAS) AF: 0.00 AC: 0 AN: 10800

South Asian (SAS) AF: 0.00152 AC: 1 AN: 658

European-Finnish (FIN) AF: 0.0370 AC: 2 AN: 54

Middle Eastern (MID) AF: 0.00216 AC: 1 AN: 464

European-Non Finnish (NFE) AF: 0.0151 AC: 708 AN: 46776

Other (OTH) AF: 0.0102 AC: 65 AN: 6342

GnomAD4 genome AF: 0.0122 AC: 1861 AN: 152300 Hom.: 16 Cov.: 32 AF XY: 0.0130 AC XY: 967 AN XY: 74474

African (AFR) AF: 0.00245 AC: 102 AN: 41582

American (AMR) AF: 0.00941 AC: 144 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4828

European-Finnish (FIN) AF: 0.0355 AC: 376 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0171 AC: 1160 AN: 68016

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0169 Hom.: 3

Bravo AF: 0.00924

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hypothyroidism, congenital, nongoitrous, 2 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.94
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: rs144041400; hg19: chr2-113974345;