17-42570011-A-T

Variant names:

• chr17-42570011-A-T
• rs665268
• NM_198204.2:c.506A>T

Variant summary

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

The NM_198204.2(MLX):​c.506A>T​(p.Gln169Leu) variant causes a missense 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. 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. Q169R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLX NM_198204.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 64 publications found

Genes affected

MLX (HGNC:11645): (MAX dimerization protein MLX) The product of this gene belongs to the family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors. These factors form heterodimers with Mad proteins and play a role in proliferation, determination and differentiation. This gene product may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors, namely, Mad1 and Mad4. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

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, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLX	NM_198204.2	c.506A>T	p.Gln169Leu	missense_variant	Exon 7 of 8	ENST00000435881.7	NP_937847.1
MLX	NM_170607.3	c.668A>T	p.Gln223Leu	missense_variant	Exon 7 of 8		NP_733752.1
MLX	NM_198205.2	c.416A>T	p.Gln139Leu	missense_variant	Exon 6 of 7		NP_937848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLX	ENST00000435881.7	c.506A>T	p.Gln169Leu	missense_variant	Exon 7 of 8	1	NM_198204.2	ENSP00000416627.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 13795

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Benign	0.0	.;M;.;.
PhyloP100		7.5
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.7	D;D;D;.
REVEL	Uncertain	0.55
Sift	Uncertain	0.010	D;T;D;.
Sift4G	Uncertain	0.046	D;D;D;D
Vest4		0.62
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.56

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: rs665268; hg19: chr17-40722029;