Genetic Variant TSC22D4:p.Arg208Leu (chr7-100477416-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030935.5(TSC22D4):c.623G>T(p.Arg208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,593,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSC22D4
NM_030935.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.227

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03175479).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030935.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC22D4	NM_030935.5	MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 2 of 5	NP_112197.1	Q9Y3Q8-1
TSC22D4-C7ORF61	NM_001395846.1		c.623G>T	p.Arg208Leu	missense	Exon 2 of 6	NP_001382775.1
TSC22D4	NM_001303043.2		c.623G>T	p.Arg208Leu	missense	Exon 2 of 5	NP_001289972.1	Q9Y3Q8-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC22D4	ENST00000300181.7	TSL:1 MANE Select	c.623G>T	p.Arg208Leu	missense	Exon 2 of 5	ENSP00000300181.2	Q9Y3Q8-1
TSC22D4	ENST00000493217.1	TSL:1	n.1268G>T		non_coding_transcript_exon	Exon 2 of 3
TSC22D4	ENST00000393991.5	TSL:2	c.-95G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 5	ENSP00000377560.1	Q9Y3Q8-2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000175

AC:

AN:

228596

AF XY:

0.0000161

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000975

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1440774

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715066

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32860

American (AMR)

AF:

0.00

AC:

AN:

41462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24704

East Asian (EAS)

AF:

0.00

AC:

AN:

39496

South Asian (SAS)

AF:

0.00

AC:

AN:

83554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52696

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101044

Other (OTH)

AF:

0.00

AC:

AN:

59332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.3

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0051

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.53

M_CAP

Benign

0.0054

MetaRNN

Benign

0.032

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.23

PrimateAI

Benign

0.45

PROVEAN

Benign

0.58

REVEL

Benign

0.078

Sift

Benign

0.17

Sift4G

Benign

0.32

Polyphen

0.0

Vest4

0.14

MutPred

0.21

Loss of methylation at R208 (P = 0.018)

MVP

0.043

MPC

0.30

ClinPred

0.020

GERP RS

-0.40

Varity_R

0.13

gMVP

0.19

Mutation Taster

=297/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over