17-42567146-C-G

Variant names:

• chr17-42567146-C-G
• rs754191585
• NM_198204.2:c.22C>G

Variant summary

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

The NM_198204.2(MLX):​c.22C>G​(p.Pro8Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,168 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. P8T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MLX NM_198204.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27797663).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLX	NM_198204.2	MANE Select	c.22C>G	p.Pro8Ala	missense	Exon 1 of 8	NP_937847.1	Q9UH92-3
	MLX	NM_170607.3		c.22C>G	p.Pro8Ala	missense	Exon 1 of 8	NP_733752.1	Q9UH92-1
	MLX	NM_198205.2		c.22C>G	p.Pro8Ala	missense	Exon 1 of 7	NP_937848.1	Q9UH92-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLX	ENST00000435881.7	TSL:1 MANE Select	c.22C>G	p.Pro8Ala	missense	Exon 1 of 8	ENSP00000416627.1	Q9UH92-3
	MLX	ENST00000246912.8	TSL:1	c.22C>G	p.Pro8Ala	missense	Exon 1 of 8	ENSP00000246912.3	Q9UH92-1
	MLX	ENST00000346833.8	TSL:1	c.22C>G	p.Pro8Ala	missense	Exon 1 of 7	ENSP00000320913.3	Q9UH92-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1114886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 530078

African (AFR) AF: 0.00 AC: 0 AN: 23556

American (AMR) AF: 0.00 AC: 0 AN: 11792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14784

East Asian (EAS) AF: 0.00 AC: 0 AN: 27600

South Asian (SAS) AF: 0.00 AC: 0 AN: 24116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3004

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 938446

Other (OTH) AF: 0.00 AC: 0 AN: 45000

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.0000241 AC: 1 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.12	T
Sift4G	Benign	0.23	T
Polyphen		0.0040	B
Vest4		0.24
MutPred		0.16		Loss of sheet (P = 0.0063)
MVP		0.94
MPC		0.32
ClinPred		0.76	D
GERP RS		6.0
PromoterAI		0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs754191585; hg19: chr17-40719164;