chr5-51387730-G-T

Position:

• chr5-51387730-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002202.3(ISL1):​c.459G>T​(p.Ala153=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ISL1 NM_002202.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 5-51387730-G-T is Benign according to our data. Variant chr5-51387730-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3048762.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISL1	NM_002202.3	c.459G>T	p.Ala153=	synonymous_variant	3/6	ENST00000230658.12
ISL1	XM_011543380.3	c.267G>T	p.Ala89=	synonymous_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISL1	ENST00000230658.12	c.459G>T	p.Ala153=	synonymous_variant	3/6	1	NM_002202.3	P1
ISL1	ENST00000511384.1	c.459G>T	p.Ala153=	synonymous_variant	3/6	5
ISL1	ENST00000505475.3	n.664G>T		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000287 AC: 42 AN: 1461824 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ISL1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.5
DANN	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs368770808; hg19: chr5-50683564; COSMIC: COSV100045048; COSMIC: COSV100045048;