17-42567146-C-T

Variant names:

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

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>T​(p.Pro8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000897 in 1,114,886 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: not found (cov: 33)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: MLX NM_198204.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.31
• Publications: 0 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=0.3506896).

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>T	p.Pro8Ser	missense	Exon 1 of 8	NP_937847.1	Q9UH92-3
	MLX	NM_170607.3		c.22C>T	p.Pro8Ser	missense	Exon 1 of 8	NP_733752.1	Q9UH92-1
	MLX	NM_198205.2		c.22C>T	p.Pro8Ser	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>T	p.Pro8Ser	missense	Exon 1 of 8	ENSP00000416627.1	Q9UH92-3
	MLX	ENST00000246912.8	TSL:1	c.22C>T	p.Pro8Ser	missense	Exon 1 of 8	ENSP00000246912.3	Q9UH92-1
	MLX	ENST00000346833.8	TSL:1	c.22C>T	p.Pro8Ser	missense	Exon 1 of 7	ENSP00000320913.3	Q9UH92-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.97e-7 AC: 1 AN: 1114886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 530078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.0000415 AC: 1 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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.29
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.050	T
Polyphen		0.42	B
Vest4		0.38
MutPred		0.14		Loss of sheet (P = 0.0063)
MVP		0.94
MPC		0.46
ClinPred		0.94	D
GERP RS		6.0
PromoterAI		0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.43
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;