chr17-42570011-A-C

Variant names:

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

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>C​(p.Gln169Pro) 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, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198204.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLX	NM_198204.2	MANE Select	c.506A>C	p.Gln169Pro	missense	Exon 7 of 8	NP_937847.1
	MLX	NM_170607.3		c.668A>C	p.Gln223Pro	missense	Exon 7 of 8	NP_733752.1
	MLX	NM_198205.2		c.416A>C	p.Gln139Pro	missense	Exon 6 of 7	NP_937848.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLX	ENST00000435881.7	TSL:1 MANE Select	c.506A>C	p.Gln169Pro	missense	Exon 7 of 8	ENSP00000416627.1
	MLX	ENST00000246912.8	TSL:1	c.668A>C	p.Gln223Pro	missense	Exon 7 of 8	ENSP00000246912.3
	MLX	ENST00000346833.8	TSL:1	c.416A>C	p.Gln139Pro	missense	Exon 6 of 7	ENSP00000320913.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.68
Sift	Benign	0.083	T
Sift4G	Uncertain	0.021	D
Polyphen		0.095	B
Vest4		0.65
MutPred		0.30		Gain of glycosylation at Q223 (P = 0.0946)
MVP		0.87
MPC		0.95
ClinPred		0.97	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.74

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;