Genetic Variant ISL1:c.*651A>T (chr5-51394261-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_002202.3(ISL1):c.*651A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 152,534 control chromosomes in the GnomAD database, including 15,658 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 15622 hom., cov: 31)

Exomes 𝑓: 0.37 ( 36 hom. )

Consequence

ISL1
NM_002202.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.609

Publications

28 publications found

Variant links:

Genes affected

ISL1 (HGNC:6132): (ISL LIM homeobox 1) This gene encodes a member of the LIM/homeodomain family of transcription factors. The encoded protein binds to the enhancer region of the insulin gene, among others, and may play an important role in regulating insulin gene expression. The encoded protein is central to the development of pancreatic cell lineages and may also be required for motor neuron generation. Mutations in this gene have been associated with maturity-onset diabetes of the young. [provided by RefSeq, Jul 2008]

ISL1 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ISL1 links:

ENSG00000288035 (HGNC:):

ENSG00000288035 links:

Genome browser will be placed here

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=-0.6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002202.3. 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
	ISL1	NM_002202.3	MANE Select	c.*651A>T		3_prime_UTR	Exon 6 of 6	NP_002193.2	P61371

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ISL1	ENST00000230658.12	TSL:1 MANE Select	c.*651A>T	3_prime_UTR	Exon 6 of 6	ENSP00000230658.7	P61371
ISL1	ENST00000967706.1		c.*651A>T	3_prime_UTR	Exon 4 of 4	ENSP00000637765.1
ENSG00000288035	ENST00000730931.1		n.*58T>A	downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

66030

AN:

151862

Hom.:

15589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.614

Gnomad AMI

AF:

0.399

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.291

Gnomad EAS

AF:

0.176

Gnomad SAS

AF:

0.312

Gnomad FIN

AF:

0.379

Gnomad MID

AF:

0.329

Gnomad NFE

AF:

0.386

Gnomad OTH

AF:

0.399

GnomAD4 exome

AF:

0.366

AC:

203

AN:

554

Hom.:

Cov.:

AF XY:

0.383

AC XY:

125

AN XY:

326

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.357

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.392

AC:

166

AN:

424

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.274

AC:

AN:

106

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.435

AC:

66110

AN:

151980

Hom.:

15622

Cov.:

AF XY:

0.428

AC XY:

31754

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.615

AC:

25462

AN:

41418

American (AMR)

AF:

0.374

AC:

5715

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1009

AN:

3470

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5174

South Asian (SAS)

AF:

0.311

AC:

1497

AN:

4806

European-Finnish (FIN)

AF:

0.379

AC:

3998

AN:

10560

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.386

AC:

26224

AN:

67960

Other (OTH)

AF:

0.395

AC:

833

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1765

3531

5296

7062

8827

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.243

Hom.:

523

Bravo

AF:

0.442

Asia WGS

AF:

0.309

AC:

1077

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.61

Mutation Taster

=100/0

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

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