Genetic Variant ISY1:c.27-125A>G (chr3-129158684-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_020701.4(ISY1):c.27-125A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,304,938 control chromosomes in the GnomAD database, including 825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: 𝑓 0.034 ( 208 hom., cov: 32)

Exomes 𝑓: 0.012 ( 617 hom. )

Consequence

ISY1
NM_020701.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.739

Publications

0 publications found

Variant links:

Genes affected

ISY1 (HGNC:29201): (ISY1 splicing factor homolog) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type catalytic step 1 spliceosome and catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ISY1 links:

ISY1-RAB43 (HGNC:42969): (ISY1-RAB43 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ISY1 (ISY1 splicing factor homolog) and RAB43 (RAB43, member RAS oncogene family) gene on chromosome 3. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product, but its C-terminus is distinct due to a frameshift relative to the downstream gene. [provided by RefSeq, Mar 2011]

ISY1-RAB43 links:

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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=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020701.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ISY1	NM_020701.4	MANE Select	c.27-125A>G	intron	N/A	NP_065752.1	Q9ULR0-3
ISY1-RAB43	NM_001204890.2		c.27-125A>G	intron	N/A	NP_001191819.1
ISY1	NM_001199469.2		c.27-125A>G	intron	N/A	NP_001186398.1	Q9ULR0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ISY1	ENST00000393295.8	TSL:1 MANE Select	c.27-125A>G	intron	N/A	ENSP00000376973.4	Q9ULR0-3
ISY1-RAB43	ENST00000418265.1	TSL:2	c.27-125A>G	intron	N/A	ENSP00000411822.1
ISY1	ENST00000273541.12	TSL:1	c.27-125A>G	intron	N/A	ENSP00000273541.8	Q9ULR0-2

Frequencies

GnomAD3 genomes

AF:

0.0344

AC:

5233

AN:

152158

Hom.:

207

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0885

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.0962

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.0215

GnomAD4 exome

AF:

0.0119

AC:

13666

AN:

1152662

Hom.:

617

AF XY:

0.0139

AC XY:

8044

AN XY:

577556

show subpopulations

African (AFR)

AF:

0.0951

AC:

2414

AN:

25392

American (AMR)

AF:

0.00534

AC:

147

AN:

27532

Ashkenazi Jewish (ASJ)

AF:

0.000843

AC:

AN:

21356

East Asian (EAS)

AF:

0.0820

AC:

2809

AN:

34266

South Asian (SAS)

AF:

0.0845

AC:

5931

AN:

70222

European-Finnish (FIN)

AF:

0.0171

AC:

669

AN:

39040

Middle Eastern (MID)

AF:

0.00878

AC:

AN:

5014

European-Non Finnish (NFE)

AF:

0.000922

AC:

812

AN:

880632

Other (OTH)

AF:

0.0167

AC:

822

AN:

49208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

614

1227

1841

2454

3068

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

212

424

636

848

1060

<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:

0.0344

AC:

5239

AN:

152276

Hom.:

208

Cov.:

AF XY:

0.0362

AC XY:

2696

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0884

AC:

3673

AN:

41536

American (AMR)

AF:

0.0144

AC:

220

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.109

AC:

564

AN:

5188

South Asian (SAS)

AF:

0.0958

AC:

463

AN:

4832

European-Finnish (FIN)

AF:

0.0171

AC:

181

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68032

Other (OTH)

AF:

0.0213

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

256

512

768

1024

1280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0147

Hom.:

Bravo

AF:

0.0346

Asia WGS

AF:

0.0790

AC:

276

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.17

(source)

DANN

Benign

0.69

PhyloP100

-0.74

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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