rs756221772

Variant names:

• chr16-54931254-C-G
• rs756221772
• NM_005853.6:c.56C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-54931254-C-G
• chr16-54931254-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005853.6(IRX5):​c.56C>G​(p.Ser19Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S19L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.42
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.771

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.56C>G	p.Ser19Trp	missense	Exon 1 of 3	NP_005844.4
	IRX5	NM_001252197.1		c.56C>G	p.Ser19Trp	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.56C>G	p.Ser19Trp	missense	Exon 1 of 3	ENSP00000378132.4	P78411-1
	IRX5	ENST00000320990.9	TSL:1	c.56C>G	p.Ser19Trp	missense	Exon 1 of 3	ENSP00000316250.5	P78411-2
	IRX5	ENST00000967637.1		c.56C>G	p.Ser19Trp	missense	Exon 1 of 3	ENSP00000637696.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245972 AF XY: 0.00

Gnomad AFR exome AF: 0.0000645

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.41		Loss of disorder (P = 0)
MVP		0.69
ClinPred		1.0	D
GERP RS		3.2
PromoterAI		0.017	Neutral
Varity_R		0.85
gMVP		0.73
Mutation Taster		=49/51	disease causing

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: rs756221772; hg19: chr16-54965166;