chr15-74175327-C-T

Variant names:

• chr15-74175327-C-T
• rs769818994
• NM_005545.4:c.469C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005545.4(ISLR):​c.469C>T​(p.Arg157Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,611,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R157S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: ISLR NM_005545.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.632
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005545.4. 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
	ISLR	NM_005545.4	MANE Select	c.469C>T	p.Arg157Cys	missense	Exon 2 of 2	NP_005536.1	O14498
	ISLR	NM_201526.2		c.469C>T	p.Arg157Cys	missense	Exon 2 of 2	NP_958934.1	O14498

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISLR	ENST00000249842.8	TSL:1 MANE Select	c.469C>T	p.Arg157Cys	missense	Exon 2 of 2	ENSP00000249842.3	O14498
	ISLR	ENST00000395118.1	TSL:1	c.469C>T	p.Arg157Cys	missense	Exon 2 of 2	ENSP00000378550.1	O14498
	ISLR	ENST00000879093.1		c.469C>T	p.Arg157Cys	missense	Exon 2 of 2	ENSP00000549152.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000322 AC: 8 AN: 248754 AF XY: 0.0000371

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1458914 Hom.: 0 Cov.: 30 AF XY: 0.0000510 AC XY: 37 AN XY: 725982

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50564

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000612 AC: 68 AN: 1111944

Other (OTH) AF: 0.000133 AC: 8 AN: 60370

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000724 AC: 3 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.63
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.58		Loss of disorder (P = 0.0372)
MVP		0.53
MPC		1.2
ClinPred		0.72	D
GERP RS		4.0
Varity_R		0.39
gMVP		0.69
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs769818994; hg19: chr15-74467668; COSMIC: COSV105858370; COSMIC: COSV105858370;