Genetic Variant TSC22D4:p.Glu221Lys (chr7-100477378-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030935.5(TSC22D4):c.661G>A(p.Glu221Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000879 in 1,592,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000081 ( 0 hom. )

Consequence

TSC22D4
NM_030935.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07

Variant links:

Genes affected

TSC22D4 (HGNC:21696): (TSC22 domain family member 4) TSC22D4 is a member of the TSC22 domain family of leucine zipper transcriptional regulators (see TSC22D3; MIM 300506) (Kester et al., 1999 [PubMed 10488076]; Fiorenza et al., 2001 [PubMed 11707329]).[supplied by OMIM, Mar 2008]

TSC22D4 links:

TSC22D4-C7ORF61 (HGNC:):

TSC22D4-C7ORF61 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05664891).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC22D4	NM_030935.5 link	c.661G>A	p.Glu221Lys	missense_variant	Exon 2 of 5	ENST00000300181.7	NP_112197.1	Q9Y3Q8-1B4DKI8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TSC22D4	ENST00000300181.7 link	c.661G>A	p.Glu221Lys	missense_variant	Exon 2 of 5	1	NM_030935.5	ENSP00000300181.2	Q9Y3Q8-1
TSC22D4	ENST00000493217.1 link	n.1306G>A		non_coding_transcript_exon_variant	Exon 2 of 3	1
TSC22D4	ENST00000393991.5 link	c.-57G>A		5_prime_UTR_variant	Exon 2 of 5	2		ENSP00000377560.1	Q9Y3Q8-2
TSC22D4	ENST00000496728.1 link	n.125G>A		non_coding_transcript_exon_variant	Exon 1 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000116

AC:

AN:

231874

Hom.:

AF XY:

0.000143

AC XY:

AN XY:

125710

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000131

Gnomad ASJ exome

AF:

0.00191

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000716

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000473

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000806

AC:

116

AN:

1440058

Hom.:

Cov.:

AF XY:

0.0000909

AC XY:

AN XY:

715146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000198

Gnomad4 ASJ exome

AF:

0.00139

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000108

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000508

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000158

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000230

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661G>A (p.E221K) alteration is located in exon 2 (coding exon 1) of the TSC22D4 gene. This alteration results from a G to A substitution at nucleotide position 661, causing the glutamic acid (E) at amino acid position 221 to be replaced by a lysine (K). 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

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

Eigen

Benign

-0.014

Eigen_PC

Benign

-0.069

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.83

M_CAP

Benign

0.016

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.61

REVEL

Benign

0.24

Sift

Uncertain

0.0040

Sift4G

Benign

0.89

Polyphen

0.96

Vest4

0.44

MVP

0.11

MPC

0.55

ClinPred

0.42

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over