chr4-105237369-A-G

Variant names:

• chr4-105237369-A-G
• rs144467609
• ENST00000305737.6:c.3427A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_017628.4(TET2):​c.3427A>G​(p.Thr1143Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1143N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TET2 NM_017628.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2 O:1
• Conservation: PhyloP100: -0.387
• Publications: 4 publications found

Genes affected

TET2 (HGNC:25941): (tet methylcytosine dioxygenase 2) The protein encoded by this gene is a methylcytosine dioxygenase that catalyzes the conversion of methylcytosine to 5-hydroxymethylcytosine. The encoded protein is involved in myelopoiesis, and defects in this gene have been associated with several myeloproliferative disorders. Two variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

TET2-AS1 (HGNC:41125): (TET2 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059254766).
• BP6: Variant 4-105237369-A-G is Benign according to our data. Variant chr4-105237369-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 135326.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00175 (267/152346) while in subpopulation AFR AF = 0.00587 (244/41586). AF 95% confidence interval is 0.00526. There are 1 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017628.4. 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
	TET2	NM_001127208.3	MANE Select	c.3409+18A>G		intron	N/A	NP_001120680.1	Q6N021-1
	TET2	NM_017628.4		c.3427A>G	p.Thr1143Ala	missense	Exon 3 of 3	NP_060098.3	Q6N021-2
	TET2-AS1	NR_126420.1		n.319-59697T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TET2	ENST00000305737.6	TSL:1	c.3427A>G	p.Thr1143Ala	missense	Exon 3 of 3	ENSP00000306705.2	Q6N021-2
	TET2	ENST00000380013.9	TSL:5 MANE Select	c.3409+18A>G		intron	N/A	ENSP00000369351.4	Q6N021-1
	TET2	ENST00000513237.5	TSL:1	c.3472+18A>G		intron	N/A	ENSP00000425443.1	E7EQS8

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 267 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.00191

GnomAD2 exomes AF: 0.000380 AC: 95 AN: 250078 AF XY: 0.000258

Gnomad AFR exome AF: 0.00530

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000168 AC: 246 AN: 1461784 Hom.: 0 Cov.: 34 AF XY: 0.000153 AC XY: 111 AN XY: 727200

African (AFR) AF: 0.00627 AC: 210 AN: 33474

American (AMR) AF: 0.000336 AC: 15 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111960

Other (OTH) AF: 0.000215 AC: 13 AN: 60392

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74510

African (AFR) AF: 0.00587 AC: 244 AN: 41586

American (AMR) AF: 0.00111 AC: 17 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000700 Hom.: 0

Bravo AF: 0.00175

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000396 AC: 48

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	TET2-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.2
DANN	Benign	0.96
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.39
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.026
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.10	T
Polyphen		0.12	B
Vest4		0.18
MVP		0.31
ClinPred		0.012	T
GERP RS		-0.84
Mutation Taster		=90/10	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: rs144467609; hg19: chr4-106158526;