NM_003466.4:c.*1457G>A

Variant names:

• chr2-113217076-C-T
• rs532372672
• NM_003466.4:c.*1457G>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.*1457G>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 0.00215 in 230,724 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (0 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.798
• 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=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00198 (301/152344) while in subpopulation NFE AF = 0.00345 (235/68040). AF 95% confidence interval is 0.00309. There are 1 homozygotes in GnomAd4. There are 139 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 301 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.*1457G>A		3_prime_UTR	Exon 12 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.*1534G>A		3_prime_UTR	Exon 12 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.*1534G>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.*1457G>A		3_prime_UTR	Exon 12 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.*1457G>A		3_prime_UTR	Exon 12 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.*1534G>A		3_prime_UTR	Exon 12 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes AF: 0.00198 AC: 301 AN: 152226 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00249 AC: 195 AN: 78380 Hom.: 0 Cov.: 0 AF XY: 0.00249 AC XY: 90 AN XY: 36122

African (AFR) AF: 0.00 AC: 0 AN: 3760

American (AMR) AF: 0.000414 AC: 1 AN: 2414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4944

East Asian (EAS) AF: 0.00 AC: 0 AN: 11108

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 66

Middle Eastern (MID) AF: 0.00212 AC: 1 AN: 472

European-Non Finnish (NFE) AF: 0.00358 AC: 173 AN: 48380

Other (OTH) AF: 0.00305 AC: 20 AN: 6552

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152344 Hom.: 1 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74490

African (AFR) AF: 0.000890 AC: 37 AN: 41588

American (AMR) AF: 0.00170 AC: 26 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00345 AC: 235 AN: 68040

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00193

Asia WGS AF: 0.000289 AC: 1 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	-0.82
CADD	Benign	11
DANN	Benign	0.68
PhyloP100		0.80
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: rs532372672; hg19: chr2-113974653;