15-74175361-C-G

Variant names:

• chr15-74175361-C-G
• rs371808969
• NM_005545.4:c.503C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005545.4(ISLR):​c.503C>G​(p.Pro168Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,610,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ISLR NM_005545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.769

Genes affected

ISLR (HGNC:6133): (immunoglobulin superfamily containing leucine rich repeat) Predicted to be involved in cell adhesion. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000261543 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2249924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISLR	NM_005545.4	c.503C>G	p.Pro168Arg	missense_variant	Exon 2 of 2	ENST00000249842.8	NP_005536.1
ISLR	NM_201526.2	c.503C>G	p.Pro168Arg	missense_variant	Exon 2 of 2		NP_958934.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISLR	ENST00000249842.8	c.503C>G	p.Pro168Arg	missense_variant	Exon 2 of 2	1	NM_005545.4	ENSP00000249842.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1458512 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 725722

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: 0.0000198

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503C>G (p.P168R) alteration is located in exon 2 (coding exon 1) of the ISLR gene. This alteration results from a C to G substitution at nucleotide position 503, causing the proline (P) at amino acid position 168 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.64
DEOGEN2	Benign	0.021	T;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	.;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.46	N;.;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.28	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.25
MutPred		0.41		Gain of solvent accessibility (P = 0.0246);Gain of solvent accessibility (P = 0.0246);Gain of solvent accessibility (P = 0.0246);
MVP		0.50
MPC		1.0
ClinPred		0.29	T
GERP RS		3.0
Varity_R		0.074
gMVP		0.73

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: rs371808969; hg19: chr15-74467702;