2-113217489-T-G

Variant names:

• chr2-113217489-T-G
• rs1478
• NM_003466.4:c.*1044A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003466.4(PAX8):​c.*1044A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 229,214 control chromosomes in the GnomAD database, including 8,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6369 hom., cov: 33)
  • Exomes 𝑓: 0.20 (1729 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.432
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-113217489-T-G is Benign according to our data. Variant chr2-113217489-T-G is described in ClinVar as Benign. ClinVar VariationId is 330868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.432 is higher than 0.05.

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.*1044A>C		3_prime_UTR	Exon 12 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.*1121A>C		3_prime_UTR	Exon 12 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.*1121A>C		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.*1044A>C		3_prime_UTR	Exon 12 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.*1044A>C		3_prime_UTR	Exon 12 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.*1121A>C		3_prime_UTR	Exon 12 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes AF: 0.270 AC: 40913 AN: 151668 Hom.: 6358 Cov.: 33

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.196 AC: 15141 AN: 77430 Hom.: 1729 Cov.: 0 AF XY: 0.197 AC XY: 7070 AN XY: 35832

African (AFR) AF: 0.408 AC: 1467 AN: 3596

American (AMR) AF: 0.183 AC: 432 AN: 2364

Ashkenazi Jewish (ASJ) AF: 0.162 AC: 795 AN: 4894

East Asian (EAS) AF: 0.0724 AC: 790 AN: 10914

South Asian (SAS) AF: 0.123 AC: 81 AN: 660

European-Finnish (FIN) AF: 0.233 AC: 113 AN: 486

Middle Eastern (MID) AF: 0.132 AC: 61 AN: 462

European-Non Finnish (NFE) AF: 0.210 AC: 9997 AN: 47644

Other (OTH) AF: 0.219 AC: 1405 AN: 6410

GnomAD4 genome AF: 0.270 AC: 40965 AN: 151784 Hom.: 6369 Cov.: 33 AF XY: 0.267 AC XY: 19776 AN XY: 74178

African (AFR) AF: 0.437 AC: 18087 AN: 41368

American (AMR) AF: 0.194 AC: 2957 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.178 AC: 617 AN: 3464

East Asian (EAS) AF: 0.109 AC: 559 AN: 5150

South Asian (SAS) AF: 0.132 AC: 632 AN: 4786

European-Finnish (FIN) AF: 0.258 AC: 2721 AN: 10556

Middle Eastern (MID) AF: 0.155 AC: 45 AN: 290

European-Non Finnish (NFE) AF: 0.215 AC: 14579 AN: 67896

Other (OTH) AF: 0.225 AC: 472 AN: 2098

Alfa AF: 0.216 Hom.: 5576

Bravo AF: 0.270

Asia WGS AF: 0.163 AC: 569 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

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	-0.66
CADD	Benign	6.9
DANN	Benign	0.88
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs1478; hg19: chr2-113975066; COSMIC: COSV54511219; COSMIC: COSV54511219;