rs146462326

Variant names:

• chr16-55326421-C-A
• rs146462326
• NM_024335.3:c.131C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-55326421-C-A
• chr16-55326421-C-G
• chr16-55326421-C-T

Variant summary

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

The NM_024335.3(IRX6):​c.131C>A​(p.Ala44Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: IRX6 NM_024335.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.65
• Publications: 1 publications found

Genes affected

IRX6 (HGNC:14675): (iroquois homeobox 6) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific; DNA-binding transcription repressor activity, RNA polymerase II-specific; and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in cell development; neuron differentiation; and regulation of transcription, DNA-templated. Predicted to act upstream of or within detection of visible light; negative regulation of transcription, DNA-templated; and retina morphogenesis in camera-type eye. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259283 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRX6	NM_024335.3	MANE Select	c.131C>A	p.Ala44Glu	missense	Exon 2 of 6	NP_077311.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRX6	ENST00000290552.8	TSL:1 MANE Select	c.131C>A	p.Ala44Glu	missense	Exon 2 of 6	ENSP00000290552.8	P78412
	IRX6	ENST00000558315.1	TSL:1	n.297C>A		non_coding_transcript_exon	Exon 2 of 5
	IRX6	ENST00000944938.1		c.131C>A	p.Ala44Glu	missense	Exon 2 of 7	ENSP00000614997.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250128 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461716 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112006

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000225 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.019	D
Sift4G	Benign	0.098	T
Polyphen		0.96	D
Vest4		0.54
MutPred		0.23		Gain of solvent accessibility (P = 0.0058)
MVP		0.94
MPC		0.14
ClinPred		0.85	D
GERP RS		5.2
Varity_R		0.24
gMVP		0.65
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs146462326; hg19: chr16-55360333; COSMIC: COSV51862207; COSMIC: COSV51862207;