rs755382547

Positions:

• chr5-51384649-C-G
• chr5-51384649-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002202.3(ISL1):​c.137C>G​(p.Ala46Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ISL1 NM_002202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISL1	NM_002202.3	c.137C>G	p.Ala46Gly	missense_variant	2/6	ENST00000230658.12	NP_002193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISL1	ENST00000230658.12	c.137C>G	p.Ala46Gly	missense_variant	2/6	1	NM_002202.3	ENSP00000230658	P1
ISL1	ENST00000511384.1	c.137C>G	p.Ala46Gly	missense_variant	2/6	5		ENSP00000422676

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 novel and predicted as disease causing by MutationTaster, scaled CADD = 23, PANTHER = probably damaging. The position of the variant amino acid is also conserved in vertebrates. The variant is inherited from unaffected mother. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.023	D;T
Sift4G	Uncertain	0.055	T;T
Polyphen		1.0	D;.
Vest4		0.54
MutPred		0.59		Loss of stability (P = 0.0967);Loss of stability (P = 0.0967);
MVP		0.73
MPC		1.2
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.50

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: rs755382547; hg19: chr5-50680483;