chr22-35082613-G-C

Position:

• chr22-35082613-G-C

Variant summary

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

The NM_001303508.2(ISX):​c.325G>C​(p.Val109Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ISX NM_001303508.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0220

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISX	NM_001303508.2	c.325G>C	p.Val109Leu	missense_variant	3/5	ENST00000404699.7
ISX	XM_047441598.1	c.325G>C	p.Val109Leu	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISX	ENST00000404699.7	c.325G>C	p.Val109Leu	missense_variant	3/5	1	NM_001303508.2	P1
ISX	ENST00000308700.6	c.325G>C	p.Val109Leu	missense_variant	2/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

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

Apr 12, 2022

The c.325G>C (p.V109L) alteration is located in exon 2 (coding exon 2) of the ISX gene. This alteration results from a G to C substitution at nucleotide position 325, causing the valine (V) at amino acid position 109 to be replaced by a leucine (L). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	5.2
DANN	Benign	0.87
DEOGEN2	Uncertain	0.56	D;D
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.82	P;P
Vest4		0.48
MutPred		0.53		Gain of catalytic residue at V109 (P = 0.0165);Gain of catalytic residue at V109 (P = 0.0165);
MVP		0.64
MPC		0.027
ClinPred		0.81	D
GERP RS		-7.6
Varity_R		0.24
gMVP		0.31

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: chr22-35478606;