22-35067212-G-A

Position:

• chr22-35067212-G-A

Variant summary

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

The NM_001303508.2(ISX):​c.125G>A​(p.Arg42Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ISX NM_001303508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0880

Genes affected

ISX (HGNC:28084): (intestine specific homeobox) Homeobox genes encode DNA-binding proteins, many of which are thought to be involved in early embryonic development. Homeobox genes encode a DNA-binding domain of 60 to 63 amino acids referred to as the homeodomain. This gene is a member of the RAXLX homeobox gene family. [provided by RefSeq, Jul 2008]

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=0.07209328).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ISX	NM_001303508.2	c.125G>A	p.Arg42Lys	missense_variant	2/5	ENST00000404699.7	NP_001290437.1
ISX	XM_047441598.1	c.125G>A	p.Arg42Lys	missense_variant	1/4		XP_047297554.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ISX	ENST00000404699.7	c.125G>A	p.Arg42Lys	missense_variant	2/5	1	NM_001303508.2	ENSP00000386037.1
ISX	ENST00000308700.6	c.125G>A	p.Arg42Lys	missense_variant	1/4	1		ENSP00000311492.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2024

The c.125G>A (p.R42K) alteration is located in exon 1 (coding exon 1) of the ISX gene. This alteration results from a G to A substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a lysine (K). 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	0.073
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.0
DANN	Benign	0.66
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.30	.;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.76	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.10
Sift	Benign	0.32	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;B
Vest4		0.059
MutPred		0.31		Gain of ubiquitination at R42 (P = 0.0016);Gain of ubiquitination at R42 (P = 0.0016);
MVP		0.68
MPC		0.010
ClinPred		0.039	T
GERP RS		-0.20
Varity_R		0.042
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-35463205;