Genetic Variant TSC22D4:p.Ser394Pro (chr7-100466967-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_030935.5(TSC22D4):c.1180T>C(p.Ser394Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,566,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

TSC22D4
NM_030935.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.23

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 -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050857365).

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.1180T>C	p.Ser394Pro	missense	Exon 5 of 5	NP_112197.1	Q9Y3Q8-1
TSC22D4	NM_001303043.2		c.1180T>C	p.Ser394Pro	missense	Exon 5 of 5	NP_001289972.1	Q9Y3Q8-1
TSC22D4-C7ORF61	NM_001395846.1		c.978+585T>C		intron	N/A	NP_001382775.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSC22D4	ENST00000300181.7	TSL:1 MANE Select	c.1180T>C	p.Ser394Pro	missense	Exon 5 of 5	ENSP00000300181.2	Q9Y3Q8-1
TSC22D4	ENST00000423266.5	TSL:2	c.499T>C	p.Ser167Pro	missense	Exon 3 of 3	ENSP00000388168.2	H7BZ77
TSC22D4	ENST00000393991.5	TSL:2	c.463T>C	p.Ser155Pro	missense	Exon 5 of 5	ENSP00000377560.1	Q9Y3Q8-2

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000987

AC:

AN:

182372

AF XY:

0.0000811

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000115

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:

0.000417

GnomAD4 exome

AF:

0.0000474

AC:

AN:

1414334

Hom.:

Cov.:

AF XY:

0.0000486

AC XY:

AN XY:

699140

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

32340

American (AMR)

AF:

0.000109

AC:

AN:

36826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24818

East Asian (EAS)

AF:

0.00

AC:

AN:

37742

South Asian (SAS)

AF:

0.00

AC:

AN:

81888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087528

Other (OTH)

AF:

0.000223

AC:

AN:

58374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000440

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41568

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000199

Hom.:

Bravo

AF:

0.000616

ExAC

AF:

0.000102

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0056

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.68

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

2.2

PrimateAI

Uncertain

0.60

PROVEAN

Benign

1.4

REVEL

Benign

0.14

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.047

Polyphen

0.0080

Vest4

0.35

MVP

0.068

MPC

0.42

ClinPred

0.067

GERP RS

3.0

Varity_R

0.15

gMVP

0.68

Mutation Taster

=91/9

polymorphism

(source)

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

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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