2-43231327-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022065.5(THADA):c.5483T>C(p.Leu1828Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L1828L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: THADA NM_022065.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

Genes affected

THADA (HGNC:19217): (THADA armadillo repeat containing) This gene is the target of 2p21 choromosomal aberrations in benign thyroid adenomas. Single nucleotide polymorphisms (SNPs) in this gene may be associated with type 2 diabetes and polycystic ovary syndrome. The encoded protein is likely involved in the death receptor pathway and apoptosis. [provided by RefSeq, Sep 2016]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26827073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THADA	NM_022065.5	c.5483T>C	p.Leu1828Pro	missense_variant	38/38	ENST00000405975.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THADA	ENST00000405975.7	c.5483T>C	p.Leu1828Pro	missense_variant	38/38	1	NM_022065.5	P1
	ENST00000423354.1	n.45-1437A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398198 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690556

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: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2023

The c.5483T>C (p.L1828P) alteration is located in exon 38 (coding exon 37) of the THADA gene. This alteration results from a T to C substitution at nucleotide position 5483, causing the leucine (L) at amino acid position 1828 to be replaced by a proline (P). 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	Benign	0.17
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	-0.0029
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.20
Sift	Benign	0.065	T;T
Sift4G	Benign	0.096	T;T
Polyphen		0.0090	B;B
Vest4		0.43
MutPred		0.51		Gain of loop (P = 3e-04);Gain of loop (P = 3e-04);
MVP		0.092
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.41
gMVP		0.75

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: rs1349315208; hg19: chr2-43458466;