1-226223773-C-G

Variant names:

• chr1-226223773-C-G
• rs1657075070
• NM_031944.3:c.92C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031944.3(MIXL1):​c.92C>G​(p.Pro31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000802 in 1,246,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. P31Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: MIXL1 NM_031944.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0710
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2116405).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031944.3. 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
	MIXL1	NM_031944.3	MANE Select	c.92C>G	p.Pro31Arg	missense	Exon 1 of 2	NP_114150.1	Q9H2W2-1
	MIXL1	NM_001282402.2		c.92C>G	p.Pro31Arg	missense	Exon 1 of 2	NP_001269331.1	Q9H2W2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIXL1	ENST00000366810.6	TSL:1 MANE Select	c.92C>G	p.Pro31Arg	missense	Exon 1 of 2	ENSP00000355775.4	Q9H2W2-1
	MIXL1	ENST00000542034.5	TSL:1	c.92C>G	p.Pro31Arg	missense	Exon 1 of 2	ENSP00000442439.1	Q9H2W2-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.02e-7 AC: 1 AN: 1246338 Hom.: 0 Cov.: 32 AF XY: 0.00000163 AC XY: 1 AN XY: 611764

African (AFR) AF: 0.00 AC: 0 AN: 24962

American (AMR) AF: 0.00 AC: 0 AN: 19072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19064

East Asian (EAS) AF: 0.00 AC: 0 AN: 26740

South Asian (SAS) AF: 0.00 AC: 0 AN: 61636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3612

European-Non Finnish (NFE) AF: 9.90e-7 AC: 1 AN: 1010556

Other (OTH) AF: 0.00 AC: 0 AN: 50578

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.00048	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.071
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.099
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.15	T
Polyphen		0.10	B
Vest4		0.15
MutPred		0.33		Loss of glycosylation at P31 (P = 0.0118)
MVP		0.48
MPC		1.4
ClinPred		0.39	T
GERP RS		1.6
PromoterAI		0.038	Neutral
Varity_R		0.073
gMVP		0.49
Mutation Taster		=92/8	polymorphism

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: rs1657075070; hg19: chr1-226411474;