NM_005853.6:c.22T>G

Variant names:

• chr16-54931220-T-G
• rs531728219
• NM_005853.6:c.22T>G

Variant summary

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

The NM_005853.6(IRX5):​c.22T>G​(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L8L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

Genes affected

IRX5 (HGNC:14361): (iroquois homeobox 5) This gene encodes a member of the iroquois homeobox gene family, which are involved in several embryonic developmental processes. Knockout mice lacking this gene show that it is required for retinal cone bipolar cell differentiation, and that it negatively regulates potassium channel gene expression in the heart to ensure coordinated cardiac repolarization. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

CRNDE (HGNC:37078): (colorectal neoplasia differentially expressed) This gene is transcribed into multiple transcript variants, some of which may function as non-coding RNAs. One of the transcript variants encodes a putative short protein that is localized to the nucleus (PMID:25978564). Expression of this locus is increased in proliferating tissues, including certain tumors such as colorectal adenomas and adenocarcinomas. Transcription from this gene is negatively regulated by insulin and insulin-like growth factors, and may regulate the expression of genes involved in metabolism. [provided by RefSeq, May 2015]

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_005853.6. 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
	IRX5	NM_005853.6	MANE Select	c.22T>G	p.Leu8Val	missense	Exon 1 of 3	NP_005844.4
	IRX5	NM_001252197.1		c.22T>G	p.Leu8Val	missense	Exon 1 of 3	NP_001239126.1	P78411-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRX5	ENST00000394636.9	TSL:3 MANE Select	c.22T>G	p.Leu8Val	missense	Exon 1 of 3	ENSP00000378132.4	P78411-1
	IRX5	ENST00000320990.9	TSL:1	c.22T>G	p.Leu8Val	missense	Exon 1 of 3	ENSP00000316250.5	P78411-2
	IRX5	ENST00000967637.1		c.22T>G	p.Leu8Val	missense	Exon 1 of 3	ENSP00000637696.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.0074
Eigen_PC	Benign	0.033
FATHMM_MKL	Benign	0.62	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.069
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.36		Gain of relative solvent accessibility (P = 0.0249)
MVP		0.51
ClinPred		0.91	D
GERP RS		2.5
PromoterAI		0.080	Neutral
Varity_R		0.41
gMVP		0.51
Mutation Taster		=61/39	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: rs531728219; hg19: chr16-54965132;