Genetic Variant NM_031944.3:c.149C>T (chr1-226223830-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031944.3(MIXL1):c.149C>T(p.Ala50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,210,668 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00053 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

MIXL1
NM_031944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.01

Publications

0 publications found

Variant links:

Genes affected

MIXL1 (HGNC:13363): (Mix paired-like homeobox) Enables RNA polymerase II-specific DNA-binding transcription factor binding activity and sequence-specific double-stranded DNA binding activity. Predicted to be involved in several processes, including endodermal cell differentiation; hematopoietic progenitor cell differentiation; and positive regulation of mesoderm development. Predicted to act upstream of or within cell migration involved in gastrulation and hemopoiesis. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MIXL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09600964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIXL1	NM_031944.3 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	ENST00000366810.6	NP_114150.1	Q9H2W2-1A0A024R3T7
MIXL1	NM_001282402.2 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2		NP_001269331.1	Q9H2W2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIXL1	ENST00000366810.6 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	1	NM_031944.3	ENSP00000355775.4		Q9H2W2-1
MIXL1	ENST00000542034.5 link	c.149C>T	p.Ala50Val	missense_variant	Exon 1 of 2	1		ENSP00000442439.1		Q9H2W2-2

Frequencies

GnomAD3 genomes

AF:

0.000526

AC:

AN:

150254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000331

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:

0.000484

GnomAD2 exomes

AF:

0.00

AC:

AN:

4390

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000528

AC:

AN:

1060306

Hom.:

Cov.:

AF XY:

0.0000435

AC XY:

AN XY:

506078

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

21424

American (AMR)

AF:

0.000251

AC:

AN:

7964

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12584

East Asian (EAS)

AF:

0.00

AC:

AN:

22546

South Asian (SAS)

AF:

0.00

AC:

AN:

22704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2956

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

908620

Other (OTH)

AF:

0.000146

AC:

AN:

41152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000525

AC:

AN:

150362

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

AN XY:

73456

show subpopulations

African (AFR)

AF:

0.00177

AC:

AN:

41332

American (AMR)

AF:

0.000331

AC:

AN:

15110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67454

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000612

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.149C>T (p.A50V) alteration is located in exon 1 (coding exon 1) of the MIXL1 gene. This alteration results from a C to T substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.46

T;T

M_CAP

Pathogenic

0.81

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.34

N;N

PhyloP100

-1.0

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.11

Sift

Benign

0.24

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.057

.;B

Vest4

0.054

MutPred

0.22

Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);

MVP

0.52

MPC

1.2

ClinPred

0.24

GERP RS

2.8

PromoterAI

0.034

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.051

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over