NM_003466.4:c.322C>T

Variant names:

• chr2-113244494-G-A
• rs104893655
• NM_003466.4:c.322C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003466.4(PAX8):​c.322C>T​(p.Arg108*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R108R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX8 NM_003466.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.18
• Publications: 5 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-113244494-G-A is Pathogenic according to our data. Variant chr2-113244494-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 13783.Status of the report is criteria_provided_single_submitter, 1 stars.

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.322C>T	p.Arg108*	stop_gained	Exon 4 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.322C>T	p.Arg108*	stop_gained	Exon 4 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.322C>T	p.Arg108*	stop_gained	Exon 4 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.322C>T	p.Arg108*	stop_gained	Exon 4 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.322C>T	p.Arg108*	stop_gained	Exon 4 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.322C>T	p.Arg108*	stop_gained	Exon 4 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.77	D
PhyloP100		1.2
Vest4		0.96
GERP RS		4.4
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs104893655; hg19: chr2-114002071;