12-122127883-A-G

Variant names:

• chr12-122127883-A-G
• NM_014938.6:c.521A>G

Variant summary

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

The NM_014938.6(MLXIP):​c.521A>G​(p.Tyr174Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLXIP NM_014938.6 missense, splice_region
• Scores: Splicing: ADA: 0.5256
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.99
• Publications: 0 publications found

Genes affected

MLXIP (HGNC:17055): (MLX interacting protein) This gene encodes a protein that functions as part of a heterodimer to activate transcription. The encoded protein forms a heterodimer with Max-like protein X (MLX) and is involved in the regulation of genes in response to cellular glucose levels. [provided by RefSeq, Mar 2014]

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, 0.816

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014938.6. 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
	MLXIP	NM_014938.6	MANE Select	c.521A>G	p.Tyr174Cys	missense splice_region	Exon 3 of 17	NP_055753.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLXIP	ENST00000319080.12	TSL:1 MANE Select	c.521A>G	p.Tyr174Cys	missense splice_region	Exon 3 of 17	ENSP00000312834.6	Q9HAP2-1
	MLXIP	ENST00000890512.1		c.521A>G	p.Tyr174Cys	missense splice_region	Exon 3 of 17	ENSP00000560571.1
	MLXIP	ENST00000890511.1		c.521A>G	p.Tyr174Cys	missense splice_region	Exon 3 of 17	ENSP00000560570.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.1	T
PhyloP100		9.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.51
Sift	Benign	0.070	T
Sift4G	Uncertain	0.060	T
Polyphen		0.67	P
Vest4		0.95
MutPred		0.46		Gain of catalytic residue at M172 (P = 0)
MVP		0.50
MPC		0.62
ClinPred		0.97	D
GERP RS		5.5
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.86
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.58
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

hg19: chr12-122612430;