Genetic Variant NM_031944.3:c.72C>A (chr1-226223753-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031944.3(MIXL1):c.72C>A(p.His24Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MIXL1
NM_031944.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.153

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18952602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIXL1	NM_031944.3 link	c.72C>A	p.His24Gln	missense_variant	Exon 1 of 2	ENST00000366810.6	NP_114150.1	Q9H2W2-1A0A024R3T7
MIXL1	NM_001282402.2 link	c.72C>A	p.His24Gln	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.72C>A	p.His24Gln	missense_variant	Exon 1 of 2	1	NM_031944.3	ENSP00000355775.4		Q9H2W2-1
MIXL1	ENST00000542034.5 link	c.72C>A	p.His24Gln	missense_variant	Exon 1 of 2	1		ENSP00000442439.1		Q9H2W2-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1277286

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

628304

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.72C>A (p.H24Q) alteration is located in exon 1 (coding exon 1) of the MIXL1 gene. This alteration results from a C to A substitution at nucleotide position 72, causing the histidine (H) at amino acid position 24 to be replaced by a glutamine (Q). 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

0.11

BayesDel_addAF

Benign

-0.050

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.32

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.32

T;T

M_CAP

Pathogenic

0.93

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.81

L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.022

D;D

Sift4G

Benign

0.29

T;T

Polyphen

0.016

.;B

Vest4

0.12

MutPred

0.21

Loss of methylation at R21 (P = 0.0525);Loss of methylation at R21 (P = 0.0525);

MVP

0.48

MPC

1.2

ClinPred

0.24

GERP RS

-0.29

Varity_R

0.060

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over