2-113246785-T-C

Position:

• chr2-113246785-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003466.4(PAX8):​c.160A>G​(p.Ser54Gly) variant causes a missense change. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S54C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PAX8 NM_003466.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.05

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_003466.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-113246785-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 436165.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 2-113246785-T-C is Pathogenic according to our data. Variant chr2-113246785-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 13787.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX8	NM_003466.4	c.160A>G	p.Ser54Gly	missense_variant	3/12	ENST00000429538.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX8	ENST00000429538.8	c.160A>G	p.Ser54Gly	missense_variant	3/12	1	NM_003466.4	P1
PAX8-AS1	ENST00000422956.6	n.36-8605T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D;D;D;.
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.96
MutPred		0.88		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.99
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs104893660; hg19: chr2-114004362;