chr16-54931410-C-T

Variant names:

• chr16-54931410-C-T
• rs773340790
• NM_005853.6:c.212C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005853.6(IRX5):​c.212C>T​(p.Pro71Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000486 in 1,440,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P71R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: IRX5 NM_005853.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.47
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40528128).

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.212C>T	p.Pro71Leu	missense	Exon 1 of 3	NP_005844.4
	IRX5	NM_001252197.1		c.212C>T	p.Pro71Leu	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.212C>T	p.Pro71Leu	missense	Exon 1 of 3	ENSP00000378132.4	P78411-1
	IRX5	ENST00000320990.9	TSL:1	c.212C>T	p.Pro71Leu	missense	Exon 1 of 3	ENSP00000316250.5	P78411-2
	IRX5	ENST00000967637.1		c.212C>T	p.Pro71Leu	missense	Exon 1 of 3	ENSP00000637696.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000486 AC: 7 AN: 1440920 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 716828

African (AFR) AF: 0.00 AC: 0 AN: 33020

American (AMR) AF: 0.00 AC: 0 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4384

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1108680

Other (OTH) AF: 0.00 AC: 0 AN: 59640

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	0.0038	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.96	P
Vest4		0.32
MutPred		0.34		Loss of disorder (P = 0.0215)
MVP		0.73
ClinPred		0.98	D
GERP RS		3.9
PromoterAI		0.0029	Neutral
Varity_R		0.27
gMVP		0.75
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs773340790; hg19: chr16-54965322;