Variant chr5-51389642-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002202.3(ISL1):c.479-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,606,088 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0050 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0051 ( 222 hom. )

Consequence

ISL1
NM_002202.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0007676

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.458

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISL1	NM_002202.3 linkuse as main transcript	c.479-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000230658.12
ISL1	XM_011543380.3 linkuse as main transcript	c.287-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
ISL1	ENST00000230658.12 linkuse as main transcript	c.479-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_002202.3	P1
ISL1	ENST00000511384.1 linkuse as main transcript	c.479-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	5
ISL1	ENST00000505475.3 linkuse as main transcript	n.684-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5

Frequencies

GnomAD3 genomes

AF:

0.00504

AC:

766

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.0715

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00241

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00914

AC:

2159

AN:

236138

Hom.:

AF XY:

0.00850

AC XY:

1101

AN XY:

129562

show subpopulations

Gnomad AFR exome

AF:

0.000483

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.00327

Gnomad EAS exome

AF:

0.0868

Gnomad SAS exome

AF:

0.00201

Gnomad FIN exome

AF:

0.0119

Gnomad NFE exome

AF:

0.00219

Gnomad OTH exome

AF:

0.00546

GnomAD4 exome

AF:

0.00510

AC:

7416

AN:

1453934

Hom.:

222

Cov.:

AF XY:

0.00504

AC XY:

3647

AN XY:

723380

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

Gnomad4 AMR exome

AF:

0.000965

Gnomad4 ASJ exome

AF:

0.00396

Gnomad4 EAS exome

AF:

0.0966

Gnomad4 SAS exome

AF:

0.00231

Gnomad4 FIN exome

AF:

0.0107

Gnomad4 NFE exome

AF:

0.00213

Gnomad4 OTH exome

AF:

0.00540

GnomAD4 genome

AF:

0.00505

AC:

768

AN:

152154

Hom.:

Cov.:

AF XY:

0.00588

AC XY:

437

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.0715

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0126

Gnomad4 NFE

AF:

0.00241

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.00468

Asia WGS

AF:

0.0320

AC:

112

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Bladder exstrophy-epispadias-cloacal extrophy complex

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Malformation Genetics, Karolinska Institutet

Sep 30, 2016

Variant is rare in the European population (gnomAD Non-Finnish Europeans f = 0.2%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Benign

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00077

dbscSNV1_RF

Benign

0.18

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over