2-113220116-G-T

Variant names:

• chr2-113220116-G-T
• NM_003466.4:c.1252C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003466.4(PAX8):​c.1252C>A​(p.Arg418Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAX8 NM_003466.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX8	NM_003466.4	c.1252C>A	p.Arg418Ser	missense_variant	Exon 11 of 12	ENST00000429538.8	NP_003457.1
PAX8	NM_013952.4	c.1173C>A	p.Gly391Gly	synonymous_variant	Exon 11 of 12		NP_039246.1
PAX8	NM_013953.4	c.942C>A	p.Gly314Gly	synonymous_variant	Exon 9 of 10		NP_039247.1
PAX8	NM_013992.4	c.840C>A	p.Gly280Gly	synonymous_variant	Exon 8 of 9		NP_054698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX8	ENST00000429538.8	c.1252C>A	p.Arg418Ser	missense_variant	Exon 11 of 12	1	NM_003466.4	ENSP00000395498.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461498 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727058

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.74	D
LIST_S2	Pathogenic	0.97	D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	.;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	.;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.87
MutPred		0.25		Gain of phosphorylation at R418 (P = 0.0343);Gain of phosphorylation at R418 (P = 0.0343);.;
MVP		0.67
MPC		0.11
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.62
gMVP		0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-113977693;