NM_001303508.2:c.82A>T

Variant names:

• chr22-35067169-A-T
• rs361863
• NM_001303508.2:c.82A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303508.2(ISX):​c.82A>T​(p.Ser28Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ISX NM_001303508.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.478
• Publications: 22 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.103627175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISX	NM_001303508.2	c.82A>T	p.Ser28Cys	missense_variant	Exon 2 of 5	ENST00000404699.7	NP_001290437.1
ISX	NM_001438732.1	c.82A>T	p.Ser28Cys	missense_variant	Exon 1 of 4		NP_001425661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISX	ENST00000404699.7	c.82A>T	p.Ser28Cys	missense_variant	Exon 2 of 5	1	NM_001303508.2	ENSP00000386037.1
ISX	ENST00000308700.6	c.82A>T	p.Ser28Cys	missense_variant	Exon 1 of 4	1		ENSP00000311492.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461160 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 726800

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111604

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.97
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.22	.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		0.48
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.059	B;B
Vest4		0.091
MutPred		0.25		Loss of phosphorylation at S28 (P = 0.0457);Loss of phosphorylation at S28 (P = 0.0457);
MVP		0.83
MPC		0.013
ClinPred		0.55	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.49
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs361863; hg19: chr22-35463162;