3-129137149-C-T

Variant names:

• chr3-129137149-C-T
• ENST00000273541.12:c.466G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001199469.2(ISY1):​c.466G>A​(p.Glu156Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ISY1 NM_001199469.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.04
• Publications: 0 publications found

Genes affected

ISY1 (HGNC:29201): (ISY1 splicing factor homolog) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in nucleus. Part of U2-type catalytic step 1 spliceosome and catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ISY1-RAB43 (HGNC:42969): (ISY1-RAB43 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ISY1 (ISY1 splicing factor homolog) and RAB43 (RAB43, member RAS oncogene family) gene on chromosome 3. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product, but its C-terminus is distinct due to a frameshift relative to the downstream gene. [provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08199686).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199469.2. 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
	ISY1	NM_020701.4	MANE Select	c.419-2195G>A		intron	N/A	NP_065752.1	Q9ULR0-3
	ISY1	NM_001199469.2		c.466G>A	p.Glu156Lys	missense	Exon 8 of 12	NP_001186398.1	Q9ULR0-2
	ISY1-RAB43	NM_001204890.2		c.419-2195G>A		intron	N/A	NP_001191819.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISY1	ENST00000273541.12	TSL:1	c.466G>A	p.Glu156Lys	missense	Exon 8 of 12	ENSP00000273541.8	Q9ULR0-2
	ISY1	ENST00000393295.8	TSL:1 MANE Select	c.419-2195G>A		intron	N/A	ENSP00000376973.4	Q9ULR0-3
	ISY1-RAB43	ENST00000418265.1	TSL:2	c.419-2195G>A		intron	N/A	ENSP00000411822.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151988 Hom.: 0 Cov.: 31

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 230130 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 109712

African (AFR) AF: 0.00 AC: 0 AN: 4132

American (AMR) AF: 0.00 AC: 0 AN: 258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1392

East Asian (EAS) AF: 0.00 AC: 0 AN: 940

South Asian (SAS) AF: 0.00 AC: 0 AN: 4480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1086

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 209892

Other (OTH) AF: 0.00 AC: 0 AN: 7508

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151988 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74230

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2082

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	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.21
DANN	Benign	0.94
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.0
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.011
Sift	Benign	0.33	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.44		Gain of ubiquitination at E156 (P = 0.0054)
MVP		0.32
MPC		0.75
ClinPred		0.065	T
gMVP		0.52
Mutation Taster		=97/3	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

hg19: chr3-128855992;