2-43230958-G-C

Variant names:

• chr2-43230958-G-C
• rs114015985
• NM_022065.5:c.5852C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_022065.5(THADA):​c.5852C>G​(p.Ala1951Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,604,270 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1951V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: THADA NM_022065.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.125
• Publications: 3 publications found

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]

LINC01126 (HGNC:49275): (long intergenic non-protein coding RNA 1126)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031399727).
• BP6: Variant 2-43230958-G-C is Benign according to our data. Variant chr2-43230958-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3043703.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022065.5. 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
	THADA	NM_022065.5	MANE Select	c.5852C>G	p.Ala1951Gly	missense	Exon 38 of 38	NP_071348.3
	THADA	NM_001083953.2		c.5852C>G	p.Ala1951Gly	missense	Exon 38 of 38	NP_001077422.1	Q6YHU6-1
	THADA	NM_001345925.2		c.5852C>G	p.Ala1951Gly	missense	Exon 39 of 39	NP_001332854.1	Q6YHU6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THADA	ENST00000405975.7	TSL:1 MANE Select	c.5852C>G	p.Ala1951Gly	missense	Exon 38 of 38	ENSP00000386088.2	Q6YHU6-1
	THADA	ENST00000405006.8	TSL:1	c.5852C>G	p.Ala1951Gly	missense	Exon 38 of 38	ENSP00000385995.4	Q6YHU6-1
	THADA	ENST00000855634.1		c.5852C>G	p.Ala1951Gly	missense	Exon 39 of 39	ENSP00000525693.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152080 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00582

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000388 AC: 96 AN: 247348 AF XY: 0.000253

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000182 AC: 265 AN: 1452072 Hom.: 2 Cov.: 31 AF XY: 0.000168 AC XY: 121 AN XY: 720392

African (AFR) AF: 0.00650 AC: 216 AN: 33256

American (AMR) AF: 0.000271 AC: 12 AN: 44262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5724

European-Non Finnish (NFE) AF: 0.00000996 AC: 11 AN: 1104450

Other (OTH) AF: 0.000367 AC: 22 AN: 59968

GnomAD4 genome AF: 0.00170 AC: 259 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74412

African (AFR) AF: 0.00588 AC: 244 AN: 41510

American (AMR) AF: 0.000720 AC: 11 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000672 Hom.: 0

Bravo AF: 0.00172

ESP6500AA AF: 0.00451 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000455 AC: 55

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	THADA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.2
DANN	Benign	0.86
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.13
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.11
Sift	Benign	0.058	T
Sift4G	Benign	0.22	T
Polyphen		0.093	B
Vest4		0.10
MVP		0.014
ClinPred		0.0048	T
GERP RS		-0.68
Varity_R		0.023
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114015985; hg19: chr2-43458097; COSMIC: COSV56699968; COSMIC: COSV56699968;