chr22-35067169-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001303508.2(ISX):​c.82A>G​(p.Ser28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,612,144 control chromosomes in the GnomAD database, including 378,382 homozygotes. 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: 𝑓 0.73 (41291 hom., cov: 31)
  • Exomes 𝑓: 0.68 (337091 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.505092E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISX	NM_001303508.2	c.82A>G	p.Ser28Gly	missense_variant	Exon 2 of 5	ENST00000404699.7	NP_001290437.1
ISX	NM_001438732.1	c.82A>G	p.Ser28Gly	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>G	p.Ser28Gly	missense_variant	Exon 2 of 5	1	NM_001303508.2	ENSP00000386037.1
ISX	ENST00000308700.6	c.82A>G	p.Ser28Gly	missense_variant	Exon 1 of 4	1		ENSP00000311492.6

Frequencies

GnomAD3 genomes AF: 0.731 AC: 111057 AN: 151908 Hom.: 41253 Cov.: 31

Gnomad AFR AF: 0.856

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.857

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.715

GnomAD2 exomes AF: 0.715 AC: 178095 AN: 249200 AF XY: 0.720

Gnomad AFR exome AF: 0.857

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.872

Gnomad FIN exome AF: 0.672

Gnomad NFE exome AF: 0.658

Gnomad OTH exome AF: 0.700

GnomAD4 exome AF: 0.676 AC: 987022 AN: 1460118 Hom.: 337091 Cov.: 47 AF XY: 0.682 AC XY: 495241 AN XY: 726330

African (AFR) AF: 0.862 AC: 28837 AN: 33466

American (AMR) AF: 0.639 AC: 28497 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 19301 AN: 26108

East Asian (EAS) AF: 0.838 AC: 33228 AN: 39666

South Asian (SAS) AF: 0.856 AC: 73734 AN: 86106

European-Finnish (FIN) AF: 0.677 AC: 36150 AN: 53382

Middle Eastern (MID) AF: 0.761 AC: 4384 AN: 5760

European-Non Finnish (NFE) AF: 0.649 AC: 720689 AN: 1110694

Other (OTH) AF: 0.699 AC: 42202 AN: 60350

GnomAD4 genome AF: 0.731 AC: 111149 AN: 152026 Hom.: 41291 Cov.: 31 AF XY: 0.735 AC XY: 54567 AN XY: 74266

African (AFR) AF: 0.856 AC: 35508 AN: 41484

American (AMR) AF: 0.677 AC: 10340 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2552 AN: 3466

East Asian (EAS) AF: 0.857 AC: 4425 AN: 5162

South Asian (SAS) AF: 0.863 AC: 4147 AN: 4808

European-Finnish (FIN) AF: 0.679 AC: 7176 AN: 10572

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44757 AN: 67954

Other (OTH) AF: 0.719 AC: 1511 AN: 2102

Alfa AF: 0.697 Hom.: 76278

Bravo AF: 0.734

TwinsUK AF: 0.642 AC: 2380

ALSPAC AF: 0.656 AC: 2529

ESP6500AA AF: 0.857 AC: 3774

ESP6500EA AF: 0.659 AC: 5667

ExAC AF: 0.720 AC: 87420

Asia WGS AF: 0.864 AC: 3004 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.666

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.026	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.0088	N
LIST_S2	Benign	0.081	.;T
MetaRNN	Benign	5.5e-7	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.3	N;N
PhyloP100		0.48
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.0	N;N
REVEL	Benign	0.22
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.025
MPC		0.010
ClinPred		0.0013	T
GERP RS		5.1
Varity_R		0.046
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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; COSMIC: COSV107352125;