PAX8 p.Phe329Leu

Variant names:

• chr2-113235494-A-T
• NM_003466.4:c.987T>A
• PAX8 p.Phe329Leu

Your query was ambiguous. Multiple possible variants found:

• chr2-113235494-A-T
• chr2-113235494-A-C
• chr2-113235496-A-G
• chr2-113235494-AAA-GAG
• chr2-113235494-AAA-TAG
• chr2-113235494-AAA-CAG

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003466.4(PAX8):​c.987T>A​(p.Phe329Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX8 NM_003466.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3210777).

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.987T>A	p.Phe329Leu	missense	Exon 9 of 12	NP_003457.1	Q06710-1
	PAX8	NM_013952.4		c.908T>A	p.Phe303Tyr	missense	Exon 9 of 12	NP_039246.1	Q06710-3
	PAX8	NM_013953.4		c.777+6057T>A		intron	N/A	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.987T>A	p.Phe329Leu	missense	Exon 9 of 12	ENSP00000395498.3	Q06710-1
	PAX8	ENST00000263334.9	TSL:1	c.987T>A	p.Phe329Leu	missense	Exon 9 of 12	ENSP00000263334.6	Q06710-1
	PAX8	ENST00000348715.9	TSL:1	c.908T>A	p.Phe303Tyr	missense	Exon 9 of 12	ENSP00000314750.5	Q06710-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.088
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.016	D
MutationAssessor	Benign	0.42	N
PhyloP100		1.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.41
Sift	Benign	0.44	T
Sift4G	Benign	0.67	T
PromoterAI		0.064	Neutral
Varity_R		0.20
gMVP		0.49
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-113993071;