chr17-40083910-G-A

Position:

• chr17-40083910-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_199334.5(THRA):​c.298G>A​(p.Asp100Asn) variant causes a missense change involving the alteration of a 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THRA NM_199334.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.98

Genes affected

THRA (HGNC:11796): (thyroid hormone receptor alpha) The protein encoded by this gene is a nuclear hormone receptor for triiodothyronine. It is one of the several receptors for thyroid hormone, and has been shown to mediate the biological activities of thyroid hormone. Knockout studies in mice suggest that the different receptors, while having certain extent of redundancy, may mediate different functions of thyroid hormone. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), THRA. . Gene score misZ 3.4693 (greater than the threshold 3.09). Trascript score misZ 4.6029 (greater than threshold 3.09). GenCC has associacion of gene with congenital nongoitrous hypothryoidism 6.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRA	NM_199334.5	c.298G>A	p.Asp100Asn	missense_variant	5/9	ENST00000450525.7	NP_955366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRA	ENST00000450525.7	c.298G>A	p.Asp100Asn	missense_variant	5/9	1	NM_199334.5	ENSP00000395641	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.298G>A (p.D100N) alteration is located in exon 5 (coding exon 4) of the THRA gene. This alteration results from a G to A substitution at nucleotide position 298, causing the aspartic acid (D) at amino acid position 100 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;D;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;.;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	-0.080	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.4	N;.;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.54	T;.;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		0.71	P;B;P;.;.
Vest4		0.74
MutPred		0.80		Loss of ubiquitination at K101 (P = 0.045);Loss of ubiquitination at K101 (P = 0.045);Loss of ubiquitination at K101 (P = 0.045);Loss of ubiquitination at K101 (P = 0.045);Loss of ubiquitination at K101 (P = 0.045);
MVP		0.99
MPC		2.2
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.18
gMVP		0.80

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: chr17-38240163;