rs1330054460

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_001303052.2(MYT1L):​c.1717G>A​(p.Gly573Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

MYT1L
NM_001303052.2 missense

Scores

11
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 7.81
Variant links:
Genes affected
MYT1L (HGNC:7623): (myelin transcription factor 1 like) This gene encodes a member of the zinc finger superfamily of transcription factors whose expression, thus far, has been found only in neuronal tissues. The encoded protein belongs to a novel class of cystein-cystein-histidine-cystein zinc finger proteins that function in the developing mammalian central nervous system. Forced expression of this gene in combination with the basic helix-loop-helix transcription factor NeuroD1 and the transcription factors POU class 3 homeobox 2 and achaete-scute family basic helix-loop-helix transcription factor 1 can convert fetal and postnatal human fibroblasts into induced neuronal cells, which are able to generate action potentials. Mutations in this gene have been associated with an autosomal dominant form of cognitive disability and with autism spectrum disorder. Alternative splicing results in multiple variants. [provided by RefSeq, Jul 2017]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYT1L. . Gene score misZ 4.7706 (greater than the threshold 3.09). Trascript score misZ 5.5162 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 39, syndromic intellectual disability.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
Variant 2-1910340-C-T is Pathogenic according to our data. Variant chr2-1910340-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 521634.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYT1LNM_001303052.2 linkuse as main transcriptc.1717G>A p.Gly573Arg missense_variant 13/25 ENST00000647738.2 NP_001289981.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYT1LENST00000647738.2 linkuse as main transcriptc.1717G>A p.Gly573Arg missense_variant 13/25 NM_001303052.2 ENSP00000497479 Q9UL68-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1459034
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
725958
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.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 39 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterApr 11, 2022- -
Likely pathogenic, criteria provided, single submitterclinical testingMolecular Genetics Lab, CHRU Brest-- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 18, 2021In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32065501, 33004838) -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 27, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.55
.;D;.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.97
D;D;D;D;.;.;D;.;D;D;D;D;D;.;.;D;.;D;D;D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Pathogenic
3.4
.;M;.;.;.;.;.;.;.;.;.;.;.;.;M;.;M;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.84
D
REVEL
Pathogenic
0.83
Polyphen
1.0
.;D;.;.;D;.;.;D;.;.;.;.;.;D;D;.;D;D;.;.;.
MutPred
0.79
.;Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);.;.;Gain of MoRF binding (P = 0.0044);.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);Gain of MoRF binding (P = 0.0044);.;.;.;Gain of MoRF binding (P = 0.0044);
MVP
0.77
MPC
3.3
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.90
gMVP
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs1330054460; hg19: chr2-1914112; API