Genetic Variant NM_030935.5:c.659C>G (chr7-100477380-G-C) – 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.659C>G(p.Ala220Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,440,984 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. A220V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

TSC22D4
NM_030935.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.134

Publications

0 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:

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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=0.048968732).

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.659C>G	p.Ala220Gly	missense	Exon 2 of 5	NP_112197.1	Q9Y3Q8-1
TSC22D4-C7ORF61	NM_001395846.1		c.659C>G	p.Ala220Gly	missense	Exon 2 of 6	NP_001382775.1
TSC22D4	NM_001303043.2		c.659C>G	p.Ala220Gly	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.659C>G	p.Ala220Gly	missense	Exon 2 of 5	ENSP00000300181.2	Q9Y3Q8-1
TSC22D4	ENST00000493217.1	TSL:1	n.1304C>G		non_coding_transcript_exon	Exon 2 of 3
TSC22D4	ENST00000393991.5	TSL:2	c.-59C>G		5_prime_UTR	Exon 2 of 5	ENSP00000377560.1	Q9Y3Q8-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000416

AC:

AN:

1440984

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32708

American (AMR)

AF:

0.00

AC:

AN:

40876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24602

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39482

South Asian (SAS)

AF:

0.00

AC:

AN:

83796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

1101762

Other (OTH)

AF:

0.00

AC:

AN:

59360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.3

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.022

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.58

M_CAP

Benign

0.0072

MetaRNN

Benign

0.049

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.13

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.4

REVEL

Benign

0.016

Sift

Uncertain

0.0020

Sift4G

Benign

0.23

Polyphen

0.32

Vest4

0.13

MutPred

0.25

Gain of catalytic residue at A220 (P = 0.0026)

MVP

0.093

MPC

0.31

ClinPred

0.12

GERP RS

-2.0

Varity_R

0.12

gMVP

0.13

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over