Genetic Variant ENST00000443053.6:c.-14A>C (chr3-50610457-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000443053.6(CISH):c.-14A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0353 in 1,551,374 control chromosomes in the GnomAD database, including 5,906 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.073 ( 1095 hom., cov: 33)

Exomes 𝑓: 0.031 ( 4811 hom. )

Consequence

CISH
ENST00000443053.6 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0450

Publications

22 publications found

Variant links:

Genes affected

CISH (HGNC:1984): (cytokine inducible SH2 containing protein) The protein encoded by this gene contains a SH2 domain and a SOCS box domain. The protein thus belongs to the cytokine-induced STAT inhibitor (CIS), also known as suppressor of cytokine signaling (SOCS) or STAT-induced STAT inhibitor (SSI), protein family. CIS family members are known to be cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by IL2, IL3, GM-CSF and EPO in hematopoietic cells. Proteasome-mediated degradation of this protein has been shown to be involved in the inactivation of the erythropoietin receptor. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

CISH links:

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new If you want to explore the variant's impact on the transcript ENST00000443053.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000443053.6. 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
	CISH	NM_145071.4	MANE Select	c.20+1174A>C		intron	N/A	NP_659508.1	Q9NSE2-1
	CISH	NM_013324.7		c.-14A>C		5_prime_UTR	Exon 2 of 4	NP_037456.5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CISH	ENST00000443053.6	TSL:1	c.-14A>C	5_prime_UTR	Exon 2 of 4	ENSP00000409346.2	Q9NSE2-3
CISH	ENST00000348721.4	TSL:1 MANE Select	c.20+1174A>C	intron	N/A	ENSP00000294173.3	Q9NSE2-1
CISH	ENST00000491847.1	TSL:1	n.1305A>C	non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0734

AC:

11157

AN:

152060

Hom.:

1089

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.330

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00967

Gnomad OTH

AF:

0.0627

GnomAD2 exomes

AF:

0.0963

AC:

15050

AN:

156318

AF XY:

0.0803

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.362

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.336

Gnomad FIN exome

AF:

0.00238

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.0688

GnomAD4 exome

AF:

0.0311

AC:

43521

AN:

1399196

Hom.:

4811

Cov.:

AF XY:

0.0292

AC XY:

20117

AN XY:

690116

show subpopulations

African (AFR)

AF:

0.131

AC:

4152

AN:

31590

American (AMR)

AF:

0.335

AC:

11977

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.0189

AC:

477

AN:

25180

East Asian (EAS)

AF:

0.324

AC:

11594

AN:

35736

South Asian (SAS)

AF:

0.0176

AC:

1394

AN:

79228

European-Finnish (FIN)

AF:

0.00272

AC:

134

AN:

49272

Middle Eastern (MID)

AF:

0.0342

AC:

191

AN:

5584

European-Non Finnish (NFE)

AF:

0.0100

AC:

10834

AN:

1078928

Other (OTH)

AF:

0.0477

AC:

2768

AN:

57976

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1940

3880

5819

7759

9699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

698

1396

2094

2792

3490

<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:

0.0735

AC:

11184

AN:

152178

Hom.:

1095

Cov.:

AF XY:

0.0766

AC XY:

5699

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.123

AC:

5115

AN:

41484

American (AMR)

AF:

0.220

AC:

3357

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3472

East Asian (EAS)

AF:

0.330

AC:

1702

AN:

5164

South Asian (SAS)

AF:

0.0292

AC:

141

AN:

4826

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00967

AC:

658

AN:

68012

Other (OTH)

AF:

0.0616

AC:

130

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

467

934

1400

1867

2334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0402

Hom.:

196

Bravo

AF:

0.0946

Asia WGS

AF:

0.141

AC:

489

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

-0.045

Mutation Taster

=300/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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