NM_003466.4:c.*2146A>G

Variant names:

• chr2-113216387-T-C
• rs895412
• NM_003466.4:c.*2146A>G

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.*2146A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 231,298 control chromosomes in the GnomAD database, including 25,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14808 hom., cov: 32)
  • Exomes 𝑓: 0.51 (10468 hom.)
• Consequence: PAX8 NM_003466.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.387
• Publications: 21 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=-0.84).
• BP6: Variant 2-113216387-T-C is Benign according to our data. Variant chr2-113216387-T-C is described in ClinVar as Benign. ClinVar VariationId is 330861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 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.*2146A>G		3_prime_UTR	Exon 12 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.*2223A>G		3_prime_UTR	Exon 12 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.*2223A>G		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.*2146A>G		3_prime_UTR	Exon 12 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.*2146A>G		3_prime_UTR	Exon 12 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.*2223A>G		3_prime_UTR	Exon 12 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64431 AN: 151930 Hom.: 14816 Cov.: 32

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.406

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.467

GnomAD4 exome AF: 0.507 AC: 40158 AN: 79250 Hom.: 10468 Cov.: 0 AF XY: 0.508 AC XY: 18528 AN XY: 36486

African (AFR) AF: 0.261 AC: 991 AN: 3792

American (AMR) AF: 0.519 AC: 1266 AN: 2438

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 2985 AN: 5026

East Asian (EAS) AF: 0.629 AC: 7055 AN: 11212

South Asian (SAS) AF: 0.532 AC: 362 AN: 680

European-Finnish (FIN) AF: 0.355 AC: 22 AN: 62

Middle Eastern (MID) AF: 0.544 AC: 260 AN: 478

European-Non Finnish (NFE) AF: 0.489 AC: 23945 AN: 48918

Other (OTH) AF: 0.492 AC: 3272 AN: 6644

GnomAD4 genome AF: 0.424 AC: 64434 AN: 152048 Hom.: 14808 Cov.: 32 AF XY: 0.428 AC XY: 31780 AN XY: 74322

African (AFR) AF: 0.246 AC: 10207 AN: 41490

American (AMR) AF: 0.525 AC: 8019 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1977 AN: 3464

East Asian (EAS) AF: 0.646 AC: 3325 AN: 5146

South Asian (SAS) AF: 0.511 AC: 2460 AN: 4812

European-Finnish (FIN) AF: 0.405 AC: 4287 AN: 10598

Middle Eastern (MID) AF: 0.613 AC: 179 AN: 292

European-Non Finnish (NFE) AF: 0.480 AC: 32622 AN: 67938

Other (OTH) AF: 0.467 AC: 988 AN: 2114

Alfa AF: 0.473 Hom.: 21937

Bravo AF: 0.427

Asia WGS AF: 0.520 AC: 1810 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	-0.84
CADD	Benign	0.80
DANN	Benign	0.75
PhyloP100		-0.39
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: rs895412; hg19: chr2-113973964;