5-2748837-A-C

Position:

• chr5-2748837-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_033267.5(IRX2):​c.871T>G​(p.Leu291Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRX2 NM_033267.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.65

Genes affected

IRX2 (HGNC:14359): (iroquois homeobox 2) IRX2 is a member of the Iroquois homeobox gene family. Members of this family appear to play multiple roles during pattern formation of vertebrate embryos.[supplied by OMIM, Apr 2004]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046414018).
• BP6: Variant 5-2748837-A-C is Benign according to our data. Variant chr5-2748837-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2569344.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRX2	NM_033267.5	c.871T>G	p.Leu291Val	missense_variant	3/4	ENST00000302057.6
IRX2	NM_001134222.2	c.871T>G	p.Leu291Val	missense_variant	3/5
IRX2	XM_011513979.3	c.871T>G	p.Leu291Val	missense_variant	3/5
IRX2	XM_024454379.2	c.592T>G	p.Leu198Val	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRX2	ENST00000302057.6	c.871T>G	p.Leu291Val	missense_variant	3/4	1	NM_033267.5	P1
IRX2	ENST00000382611.10	c.871T>G	p.Leu291Val	missense_variant	3/5	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Benign	0.51
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.065	N
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;N
MutationTaster	Benign	0.96	N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.52	N;N
REVEL	Benign	0.17
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.090
MutPred		0.26		Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);
MVP		0.14
MPC		0.43
ClinPred		0.056	T
GERP RS		3.6
Varity_R		0.24
gMVP		0.13

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-2748951;