rs361863

chr22-35067169-A-Cchr22-35067169-A-Gchr22-35067169-A-T

Variant summary

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

The NM_001303508.2(ISX):c.82A>C(p.Ser28Arg) 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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S28G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ISX NM_001303508.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.478

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=0.07810038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISX	NM_001303508.2	c.82A>C	p.Ser28Arg	missense_variant	2/5	ENST00000404699.7
ISX	XM_047441598.1	c.82A>C	p.Ser28Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISX	ENST00000404699.7	c.82A>C	p.Ser28Arg	missense_variant	2/5	1	NM_001303508.2	P1
ISX	ENST00000308700.6	c.82A>C	p.Ser28Arg	missense_variant	1/4	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.043	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.0	B;B
Vest4		0.066
MutPred		0.23		Gain of MoRF binding (P = 0.0161);Gain of MoRF binding (P = 0.0161);
MVP		0.82
MPC		0.010
ClinPred		0.65	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs361863; hg19: chr22-35463162;